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FGF23 in type 2 diabetic patients: relationship with bone metabolism and vascular disease. Keywords: cytokine, glucose metabolism, lipid metabolism, insulin resistance, inflammation. Citation: Shi J, Fan J, Su Q and Yang Z Cytokines and Abnormal Glucose and Lipid Metabolism.

Received: 28 June ; Accepted: 30 September ; Published: 30 October Copyright © Shi, Fan, Su and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY.

The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. cn ; Zhen Yang, yangzhen xinhuamed. Importantly, as metabolic regulation by glucose occurs mainly at the transcriptional level [22] , we assessed the mRNA levels of target genes involved in glucose transport, glycolysis, gluconeogenesis, lipogenesis and fatty acid β-oxidation, in liver and muscle, at the three post-injection time intervals.

It was approved by the Direction Departementale des Services Veterinaires French veterinary services to carry out animal experiments INRA —36, April 14th, The INRA experimental station is certified for animal services under the permit number A The study was conducted with two lines of rainbow trout Oncorhynchus mykiss , Walbaum , designated as Lean line L and Fat line F , obtained after five generations of divergent selection for high or low muscle fat content using a nondestructive method Distell Fish Fatmeter as detailed by Quillet et al.

Muscle fat content was found more than 3 times higher in the F line than in the L in g-trout of this fifth generation [37]. Fish were kept unfed for 48 h before the time of treatment in order to obtain fish with basal levels of plasma metabolites and an empty digestive tract.

Fish were lightly anaesthetized with 0. Blood was quickly removed from the caudal vein using syringes rinsed with an anticoagulant 0.

All fish were sampled at the expected time ±5 min. Frozen samples of liver mg and muscle mg were homogenized in 2 ml of buffer containing mM NaCl, 10 mM Tris, 1 mM EGTA, 1 mM EDTA pH 7.

Tubes were kept in ice during the whole process to avoid protein denaturation. Homogenates were centrifuged at g for 15 min at 4°C and supernatants were again centrifuged at 20, g for 30 min. The concentration of protein in each sample was determined using Bio-Rad protein assay kit Bio-Rad Laboratories, Munich, Germany with bovine serum albumin as standard.

Liver and muscle protein lysates 10 µg of protein for Akt; 20 µg for AMPK were subjected to SDS-PAGE and Western blotting using appropriate antibodies. Anti-phospho Akt Ser , anti-carboxyl terminal Akt, anti-phospho AMPK Thr and anti-AMPK antibodies were used Cell signaling Technology, Saint Quentin Yvelings, France.

All these antibodies have been shown to cross-react successfully with rainbow trout proteins of interest [16] , [33]. After washing, membranes were incubated with an IRDye infrared secondary antibody LI-COR Biosciences and spots were quantified by Odyssey Infrared Imaging System software Version 3.

One microgram of the resulting total RNA was reverse transcribed into cDNA using the SuperScript III RNaseH-reverse transcriptase kit Invitrogen and random primers Promega, Charbonnières, France according to the instructions of each manufacturer, including no RNA and no reverse transcriptase control.

Target gene expression levels were determined by quantitative real-time RT-PCR, using specific primers [32] , [33] , [39] , [40]. Quantitative RT-PCR was carried out on a LightCycle II Roche Diagnostics, Neuilly-sur-Seine, France using SYBR Green I Master Roche Diagnostics GmbH, Mannheim, Germany.

The transcripts assessed were glucokinase GK , 6-phosphofructokinase 6PFK and pyruvate kinase PK for glycolysis; glucosephosphatase G6Pase1 and G6Pase2 , fructose 1,6-bisphosphatase FBPase and phosphoenolpyruvate carboxykinase PEPCK for gluconeogenesis; glucose facilitative transporter type 2 GLUT2 and 4 GLUT4 for glucose transport; sterol regulatory element binding protein 1c SREBP1c for transcription factor regulating lipogenesis; glucose 6-phosphate dehydrogenase G6PD , ATP citrate lyase ACLY , acetyl-CoA carboxylase ACC and fatty acid synthase FAS for de novo lipogenesis; carnitine palmitoyl transferase 1 CPT1a and CPT1b , 3-hydroxyacyl-CoA dehydrogenase HOAD and acyl-CoA oxidase ACO for fatty acid β-oxidation.

No template control was applied for each primer. Relative quantification of target gene expression was performed using the mathematical model described by Pfaffl [41].

Results are mostly expressed as means ± SD. When an interaction was significant, means were compared using the Student-Newman-Keuls multiple comparison test. Plasma concentration of specific metabolites at 3, 8 and 12 h after intraperitoneal injection of glucose or saline solution are presented in Table 1.

In both lines, glucose administration resulted in a pronounced and persistent hyperglycemia, as observed at 3 h post-injection. Thereafter at 8 h post-injection, glycemia had returned to basal values. However, L line exhibited hyperglycemia again at 12 h after glucose treatment, in contrast to the normal glycemia observed in F line.

Plasma triglycerides followed a time-response pattern similar to glycemia profile in L line at 12 h post-glucose treatment. In the saline injected fish, F line was found to have higher plasma triglyceride and free fatty acid levels than L line, but no such genotypic difference was observed in the glucose treated fish.

Regarding tissue glycogen content Fig. Glucose treatment was linked to liver glycogen depletion in L line, whereas in F line, it was associated with unaltered liver glycogen content in F line. With regard to glycogen content in muscle, a slight but not significant decrease was found in L line, whereas an inverse effect was observed in F line.

In case of interaction, mean values not sharing a common lowercase letter are significantly different from each other. Changes in the phosphorylation status of components of the insulin signaling pathway Akt-TOR and major cellular energy sensor AMPK were analyzed in the liver and muscle of the two trout lines sampled 3 h after treatment, using Western blot.

No significant difference was noted in the ratio of phosphorylated to total protein of Akt and AMPK between the two genotypes as well as treatment, in both liver and muscle Fig.

Western blots were performed on 6 individual samples per treatment and a representative blot is shown here. Relative fold difference in the mRNA levels of hepatic glycolytic enzymes at 3, 8 and 12 h post-injection is shown in Fig.

Compared to L line, the transcripts of 6PFK and PK were also more abundant in the F line at 8 h post-injection, irrespective of saline or glucose treatment. Hepatic PK expression however remained enhanced in F line at 12 h. GLUT2 mRNA level in the liver was not modified by glucose treatment and did not vary between the two genotypes.

Glucokinase GK , 6-phosphofructokinase 6PFK , pyruvate kinase PK and glucose transporter type 2 GLUT2 mRNA levels were measured using real-time quantitative RT-PCR. Expression values were normalized by 18S-ribosomal RNA transcripts.

Relative transcript levels of key gluconeogenic enzymes in the liver are presented in Fig. In both lines, glucose treatment was associated with a decrease in the expression of G6Pase1 at 8 h post-injection, but conversely it was found to enhance the expression of FBPase and PEPCK at 3 h post-injection.

Particularly, PEPCK transcripts were more abundant in F line than L line, irrespective of treatment. In addition, disordinal interaction between treatment and line was observed for G6Pase1, G6Pase2 and FBPase mRNA levels at 3 h post-injection, where glucose loading up-regulated the expression of these enzymes specifically in the L line.

Glucosephosphatase isoform 1 G6Pase1 and isoform 2 G6Pase2 , fructose 1,6-bisphosphatase FBPase and phosphoenolpyruvate carboxykinase PEPCK mRNA levels were measured using real-time quantitative RT-PCR. Concerning the expression of glycolytic markers in white muscle Fig. Apart from that, no other changes were found in the transcript levels of HK, 6PFK, PK and GLUT4 due to treatment or genotype.

Hexokinase HK , 6-phosphofructokinase 6PFK , pyruvate kinase PK and glucose transporter type 4 GLUT4 mRNA levels were measured using real-time quantitative RT-PCR.

Expression values were normalized by β-actin-transcripts. As represented in Fig. Similar induction was observed also for ACLY expression, but only in the L line, leading to a significant interaction.

Transcripts of SREBP1c, ACC and FAS were not significantly influenced by the glucose load. Except for an enhanced expression of ACC in the F line at 8 h post-injection, no genotypic difference was noted in the target lipogenic markers. Concerning fatty acid β-oxidation in the liver Fig.

Disordinal treatment × line interaction was observed in HOAD and ACO expression at 3 h post treatment, with a significant induction in the L line after a glucose load. Sterol regulatory element binding protein 1c SREBP1c , glucose 6-phosphate dehydrogenase G6PD , ATP citrate lyase ACLY , acetyl-CoA carboxylase ACC and fatty acid synthase FAS mRNA levels were measured using real-time quantitative RT-PCR.

Carnitine palmitoyl transferase isoform 1 a CPT1a and b CPT1b , 3-hydroxyacyl-CoA dehydrogenase HOAD and acyl-CoA oxidase ACO mRNA levels were measured using real-time quantitative RT-PCR.

Mean values not sharing a common lowercase letter are significantly different from each other. Changes in relative mRNA levels of key enzymes involved in muscle fatty acid oxidation are shown in Fig.

Glucose administration was found to down-regulate the expression of CPT1 isoforms, HOAD and ACO in both lines, at 3 or 12 h post-injection, irrespective of the treatment. F line exhibited consistently higher CPT1a expression than L line at all the post-injection time points.

Similar genotypic difference was observed also in the transcript levels of CPT1b and HOAD at 12 h post-injection. Finally, a significant treatment × line interaction was observed in ACO expression at 3 h post-injection, where glucose loading reduced ACO expression specifically in F line.

Previous nutritional studies in the two selected trout lines suggested that the F line displayed a higher ability to metabolize glucose and to synthesize lipids de novo than the L line [16] , [32] , [33].

We thus postulated that the F line has a better capability to maintain glucose homeostasis after a dietary glucose load than L line. To check this hypothesis, the two rainbow trout lines were intraperitoneally injected with glucose or saline solution to investigate the genotypic differences in the regulation of glucose and lipid metabolism after a high glucose flux.

This study is clearly different from our previous study based on the use of dietary carbohydrates [16] related to the route of the glucose supplementation intake of dietary carbohydrates [16] versus intraperitoneal glucose injection and the nutritional status of the fish fed fish [16] versus unfed fish.

Moreover, the present study describes the potential differential regulation of metabolism by glucose between two rainbow trout lines which is highly interesting for a better understanding of the glucose use in carnivorous animals.

The time-dependent regulation of metabolic gene expression by glucose is different for each gene: some are differentially expressed already 3 h after injection the hepatic gluconeogenic genes for example and others are differently expressed only 12 h after injection fatty acid oxidation genes in muscle for example suggesting that the genes are not regulated by glucose with similar molecular mechanisms.

As expected, a strong and persistent hyperglycemia was induced after glucose treatment in both rainbow trout lines, confirming the poor ability of this species to regulate glucose homeostasis [19] , [42].

The high glycemia had no effect on the mRNA levels of hepatic glucose transporter GLUT2, probably due to the fact that this gene is present constitutively in the plasma membrane [43].

Moreover, the expression of GLUT2 has been observed to be high in rainbow trout, irrespective of the nutritional status [44]. Concerning hepatic glycolysis, Borrebaek et al. reported that high starch content in the diet up-regulated GK activity in Atlantic salmon [45].

Similarly in rainbow trout, a strong induction of GK expression was observed following the intake of a carbohydrate rich diet [42]. With respect to gluconeogenesis, glucose was found to enhance the transcript levels of FBPase and PEPCK in the liver of both trout lines, reinforcing the fact that in carnivorous fish, glucose does not exert a mammalian like inhibitory effect on the gluconeogenic pathway [16] , [44] , [46] , [47].

In particular, the augmentation of the gluconeogenic potential that we observed after a glucose load in these two trout lines, have also been described in other carnivorous fish such as red sea bream and yellowtail [14]. Nevertheless, in concordance with the lowered glycemic values at 8 h after glucose treatment, hepatic G6Pase was found to be down-regulated in both lines.

In the white skeletal muscle of the glucose treated fish from both lines, we observed a paradoxical decrease in the expression of HK, which indicates an atypical regulation of muscle glucose metabolism in response to high influx of glucose, corroborating previous finding in salmonids [16] , [19].

This observation also serves as an evidence for the poor capacity of glucose utilization in the peripheral tissues of carnivorous fish [1] , irrespective of the genotype. Regarding the genotype effect, F line apparently had a more efficient and stable glucose clearance mechanism to deal with a glucose load than L line, in agreement with previous findings that reported significantly lower levels of glucose in the F line at 24 h after refeeding [33].

Moreover, the return of plasma glucose level to basal values at 8 h after glucose treatment in F line was relatively much faster than the 24 h glycemia recovery period previously reported in rainbow trout, after administering a similar dose of glucose [7].

These differences in glycemia profiles between the two lines after glucose challenge could be due to genetic difference as a side effect of the selection for the target trait, i.

the muscle fat content. Even if the existence of a genetic component that would determine the ability to utilize glucose is unknown in fish, it can be hypothesized, as suggested by the variation in glucose tolerance among three natural strains of Chinook salmon [30] and by selectively bred fast growing families of rainbow trout which have higher plasma insulin levels than their slow growing counterparts [48].

The higher efficiency of plasma glucose clearance in F line was basically associated with its enhanced hepatic glycolytic potential higher transcript levels of GK, 6PFK and PK , consistent with previous observations [16] , [32].

Overall, these data suggest that genetic selection could be a determinant of glucose homeostasis as in Chinook salmon [30]. However, it is important to note that, the transcript levels of gluconeogenic enzyme PEPCK were also higher in F line, suggesting a greater endogenous glucose synthesis potential than in L line.

Concomitant weaker control of gluconeogenesis and enhanced glycolytic potential was similarly observed in the 4th generation F line fish, irrespective of dietary carbohydrate levels [16]. In fish, liver is the major tissue that regulates glucose disposal [49] and generally, hepatic glycogen content is higher in fish fed a carbohydrate-rich diet than in those fed a carbohydrate-free diet due to excess glucose storage [4] , [50].

With respect to tissue glycogen deposition in both lines, we observed a significant interaction between glucose treatment and genotype in both liver and muscle. The hyperglycemia found in L line at 12 h after glucose treatment can be probably explained by an apparent lower glycolytic potential in the liver of this line compared to the F line concomitantly with a decreased potential of glycogen synthesis in liver at 8 h post-injection.

This in turn may be related to the lower muscle lipid content, i. On the other hand, normoglycemia was observed in F line at 12 h post-injection, in concordance with a slight but not statistically significant increase in muscle glycogen deposition.

These cumulative findings endorse our hypothesis that F line has a better ability to maintain glucose homeostasis than L line. Lipogenesis possibly plays a crucial role in the glucose homeostasis of rainbow trout, by converting excess glucose into lipids [4].

G6PD and ACLY are the key enzymes that provide NADPH for fatty acid biosynthesis and divert glycolytic carbon flux into lipid biosynthesis, respectively. We found that glucose administration enhanced the transcript levels of G6PD and ACLY, but not those of FAS and SREBP1c, similar to the observation made after long term feeding of a carbohydrate rich diet in the 4th generation fish [16].

The absence of induction of SREBP1c and FAS expression after glucose treatment in the present study might be partly related to the 48 h-fasting applied before injection.

In mammals, glucose uptake inhibits fatty acid oxidation, both in mitochondria and peroxisome due to insulin secretion and action [52] , [53]. This discrepancy may be caused by the experimental differences between the two studies: intake of dietary carbohydrates [16] may be able to induce insulin secretion related to increase of blood glucose plus other incretin factors glucose-dependent insulinotropic polypeptide GIP and glucagon-like peptide 1 GLP-1 for example [54] which are not present after glucose injection.

Furthermore, glucose is known to stimulate hepatic lipolysis in rainbow trout, both in vivo and in vitro , by enhancing the activity of lipolytic enzymes [55] , [56].

Somatostatin was found to mediate the stimulation of hepatic lipolysis in several species such as rainbow trout, coho salmon and lamprey [57] , [58]. Hence, the glucose enhanced HOAD mRNA levels that we observed, might be resulting from elevated plasma somatostatin concentration.

The effect of glucose treatment on muscle fatty acid oxidation was different from our observations in the liver, confirming tissue specific regulation [59]. Expression of the genes encoding the fatty acid oxidation enzymes, i. CPT1a, CPT1b, HOAD and ACO were significantly inhibited by glucose in the muscle, differing from earlier reports of inertness in rainbow trout fed a high carbohydrate diet [16] , [27] , [59].

intake of a high carbohydrate diet and the nutritional status of the fish fasted vs. Inhibition of fatty acid oxidation markers when coupled together with the decrease in the level of plasma triglycerides, suggests that the external glucose load might trigger a switch from the use of fatty acids as fuel in fasted fish to the use of glucose as fuel in glucose treated fish.

In contrast to the higher lipogenic potential demonstrated in F line of the previous generation [16] , [33] , we found no genotypic differences in the target genes related to de novo lipogenesis, except for an elevated expression of ACC in the F line. Thus, the higher muscle fat content in F line cannot be strictly attributed to its lipogenic ability, as previously noted [32].

Likewise, increased muscle fat content in F line is also not due to a decrease in fatty acid oxidation capacity [32]. Conversely, we found an enhanced fatty acid oxidation potential especially at the fatty acid transport level with CPT1 in the liver and muscle of F line, contrary to our previous observations [16] , [32] , [33].

Even though we cannot eliminate a putative difference linked to the generation of selection 5th vs. Indeed, unfed fish use fatty acids as the preferential energy source [60] in contrast to fed fish; we can hypothesize that fatty acid potential could be strongly changed in this context in the fish lines.

Previous studies demonstrated that there were very few line × diet interactions for the markers of lipid metabolism in both 3rd and 4th generations of selection [16] , [32]. In agreement with this, limited but significant interactions were observed between glucose treatment and genotype in the hepatic expression of ACLY, HOAD and ACO, where glucose specifically enhanced their expression in the L line.

In particular, we can say that glucose affects hepatic fatty acid oxidation markers in a genotype specific manner. The present study mainly reveals the differences in the transcriptional regulation of glucose and lipid metabolism after a GTT between two genotypes of rainbow trout.

In both lines, intraperitoneal administration of glucose led to a prolonged hyperglycemia, this relative inability to utilize high levels of glucose was associated with a lack of regulation of gluconeogenesis.

However, compared to L line, regulation of glycemia was more stable in F line, linked to higher muscle glycogen content and an enhanced expression of glycolytic gene markers in the liver, after glucose treatment. Some of these observations are coherent with the findings of previous nutritional challenge studies [16] , [32] , [33] and support our hypothesis that the F line has a higher capability to maintain glucose homeostasis after a glucose load than the L line.

Our data are also helpful for understanding glucose use in carnivorous fish. Therefore, genetic selection is apparently a possible way to modify the poor capability of glucose hemostasis in carnivorous fish, primarily by influencing the regulation of key enzymes involved in glucose and lipid metabolism.

We thank W. Dai and T. Cerezo for sampling assistance. We thank K. Dias, A. Surget and A. Herman for technical assistance in the laboratory.

We also acknowledge the technical staff of the INRA experimental fish farm at Lees-Athas P. Maunas and N. Turonnet for fish rearing. Conceived and designed the experiments: SP FM.

Performed the experiments: JJ PA VV. Analyzed the data: JJ SP FM. Contributed to the writing of the manuscript: JJ SP FM BSK. Browse Subject Areas?

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Planas, Universitat de Barcelona, Spain Received: March 31, ; Accepted: July 23, ; Published: August 20, Copyright: © Jin et al. Introduction Compared to mammals that have the ability to deal rapidly with a glucose load or a diet rich in carbohydrates, carnivorous teleost are generally recognized as poor users of glucose [1] — [4].

Experimental design and sampling procedure The study was conducted with two lines of rainbow trout Oncorhynchus mykiss , Walbaum , designated as Lean line L and Fat line F , obtained after five generations of divergent selection for high or low muscle fat content using a nondestructive method Distell Fish Fatmeter as detailed by Quillet et al.

Statistical analysis Results are mostly expressed as means ± SD. Results Plasma metabolites levels Plasma concentration of specific metabolites at 3, 8 and 12 h after intraperitoneal injection of glucose or saline solution are presented in Table 1.

Download: PPT. Table 1. Tissue glycogen content Regarding tissue glycogen content Fig. Figure 1. Glycogen content in liver A and muscle B of rainbow trout from L line L; grey bars and F line F; black bars , 3 h after IP administration of glucose Glu or saline Sal solution.

Insulin signaling pathway and cellular energy sensor AMPK Changes in the phosphorylation status of components of the insulin signaling pathway Akt-TOR and major cellular energy sensor AMPK were analyzed in the liver and muscle of the two trout lines sampled 3 h after treatment, using Western blot.

Figure 2. Western blot analysis of AMPK and Akt phosphorylation in rainbow trout liver A and muscle B samples from L line L; grey bars and F line F; black bars , 3 h after IP administration of glucose or saline solution.

Messenger RNA levels of target genes Relative fold difference in the mRNA levels of hepatic glycolytic enzymes at 3, 8 and 12 h post-injection is shown in Fig.

Figure 3. Gene expression of selected glycolytic enzymes and glucose transporter in the liver of rainbow trout from L line L; grey bars and F line F; black bars at 3 h A , 8 h B and 12 h C after IP administration of glucose or saline solution. Figure 4. Gene expression of selected gluconeogenic enzymes in the liver of rainbow trout from L line L; grey bars and F line F; black bars at 3 h A , 8 h B and 12 h C after IP administration of glucose or saline solution.

Figure 5. Gene expression of selected glycolytic enzymes and glucose transporter in the muscle of rainbow trout from L line L; grey bars and F line F; black bars at 3 h A , 8 h B and 12 h C after IP administration of glucose or saline solution.

Figure 6. Gene expression of selected transcription factors and enzymes involved in NADPH generation and lipogenesis in the liver of rainbow trout from L line L; grey bars and F line F; black bars at 3 h A , 8 h B and 12 h C after IP administration of glucose or saline solution.

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We apologise to all the researchers whose work was omitted because of constraints on the number of references. We would like to thank C. Loracher for intensive discussion of the subject. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee , , Nuthetal, Germany.

Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité-University-Medicine Berlin, Berlin, Germany.

You can also search for this author in PubMed Google Scholar. Correspondence to M. Reprints and permissions. Weickert, M. Signalling mechanisms linking hepatic glucose and lipid metabolism.

Diabetologia 49 , — Download citation. Received : 04 November Accepted : 03 February Published : 23 May Issue Date : August Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Download PDF. Abstract Fatty liver and hepatic triglyceride accumulation are strongly associated with obesity, insulin resistance and type 2 diabetes, and are subject to nutritional influences.

Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease Article Open access 26 June The mechanisms of action of metformin Article Open access 03 August Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice Article Open access 10 February Use our pre-submission checklist Avoid common mistakes on your manuscript.

Introduction The exact mechanisms that link obesity, impaired glucose metabolism, hepatic lipid accumulation and insulin resistance are unknown, but our knowledge is rapidly increasing. Role of the liver in glucose metabolism In the liver, insulin regulates fasting glucose concentrations by inhibiting hepatic glucose production and stimulating glycogen synthesis.

Role of the liver in lipid metabolism Consistent with its function as an anabolic hormone, insulin promotes the synthesis, and inhibits the degradation of lipids. Acute vs prolonged exposure to insulin Insulin is commonly viewed as a positive regulator of fatty acid synthesis, as it promotes the expression of FASN and ACAC.

Full size image. Concluding remarks The studies discussed in this review indicate that hepatic fat accumulation, insulin resistance and disturbed glucose metabolism are inter-related at a molecular level.

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Author information Authors and Affiliations Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee , , Nuthetal, Germany M.

Pfeiffer Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité-University-Medicine Berlin, Berlin, Germany M.

As fat accumulates, there is an ongoing increase in the levels of plasma FFAs, which causes insulin resistance. In addition, the deficit of another product of adipose tissue e.

To counter insulin resistance and prevent hyperglycemia, insulin levels increase. In individuals with a genetic predisposition for diabetes, however, the pancreas cannot compensate for the increased secretory demands placed on it, resulting in type 2 diabetes.

The pivotal role of FFAs in the development of insulin resistance and type 2 diabetes suggests that the optimal therapeutic intervention should decrease plasma FFA levels. The PPAR family is intimately involved in lipid metabolism.

Two subtypes of these receptors are the site of action of synthetic PPAR agonists: PPAR-α and PPAR-γ. The former increases fatty acid oxidation, whereas the latter results in the redistribution of fat from visceral to subcutaneous body fat and an increase in adiponectin.

The outcome of activation of PPAR-γ is a lowering of plasma FFA concentrations and improved insulin sensitivity.

The effects of PPAR-α on lipid metabolism may also bring about improvements in insulin sensitivity. The currently available PPAR agonists selectively activate either PPAR-α i. Potential mechanism of FFA on insulin resistance and atherogenesis in human muscle. The key initiating event is an increase in plasma FFA followed by increased uptake of FFA into muscle.

This leads to intramyocellular accumulation of fatty acyl-CoA and DAG and activation of PKC the β II and δ isoforms. It is assumed that activation of PKC interrupts insulin signaling by serine phosphorylation of IRS-1, resulting in a decrease in tyrosine phosphorylation of IRS PI, phosphatidylinositol.

This work was supported by National Institutes of Health Grants RAG, RDK, RHL, and RDK and a Mentor-Based Training Grant from the American Diabetes Association all to G.

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FFAs AND INSULIN SECRETION. Article Information. Article Navigation. Lipids and Glucose in Type 2 Diabetes : What is the cause and effect? Guenther Boden, MD ; Guenther Boden, MD.

This Site. Google Scholar. Markku Laakso, MD Markku Laakso, MD. Address correspondencereprint requests to G. Boden, MD, Temple University Hospital, N.

Broad St. E-mail: bodengh tuhs. Diabetes Care ;27 9 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Figure 1—. View large Download slide. Figure 2—. Potential contributions of PPAR-α and PPAR-γ to improvements in insulin sensitivity.

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Proc Natl Acad Sci U S A. Fatty acid ω-oxidation occurs in the endoplasmic reticulum of some cells, especially in the liver and kidney This process involves the monooxygenase-catalyzed oxidation of the fatty acid ω-carbon the carbon furthest from the carboxyl group , followed by successive oxidations of the β-carbon until the fatty acid chain is shortened by two carbon atoms.

This mechanism exists to break down large, water-insoluble fatty acids that, in greater quantities, would be hazardous to cells The ω-oxidation of fatty acids accelerates the rate of fatty acid degradation as feedback to various stressors such as hypoxia, inflammation, and stimulation by exogenous substances.

These substances increase the demand for FAO and detoxification. Correspondingly, the omega-oxidation of fatty acids reduces the likelihood that these stressors will lead to senescence and age-related diseases.

Triglycerides, phospholipids, sphingolipids, and cholesterol lipids are all produced by a series of enzymatic reactions between fatty acids and different chemical groups. Therefore, the regulation of fatty acid synthesis affects the metabolic homeostasis of lipids to a certain extent.

Acetyl-CoA carboxylase ACC catalyzes the rate-limiting step of de novo fatty acid synthesis Among the two subtypes, ACC1 and ACC2, the former locates in the cytoplasm and is used for fatty acid synthesis by converting acetyl coenzyme A into malonyl coenzyme A.

ACC2 is located on the cytoplasmic surface of mitochondria, and the product is used to inhibit CPT1 from reducing FAO SiRNA silencing of SREBP1 significantly reduced the expression of its downstream target genes ACC , FAS , and ATP citrate lyase, and weakened H 2 O 2 -induced senescence ACC1-dependent lipogenesis is the fundamental metabolic pathway downstream of AMPK, which induces autophagy and maintains cell survival during yeast senescence This evidence suggests that ACC directly modulates the senescence phenotype, and several drugs targeting ACC to slow senescence already exist.

Citrate treatment can increase ACC1 expression, promote excessive lipid biosynthesis, and lead to tumor cell senescence and growth inhibition The AD candidate drugs CMS and J play anti-senescence neuroprotective roles by inhibiting ACC1 and increasing acetyl-CoA levels Resveratrol plays an anti-senescence role by increasing ACC phosphorylation and enhancing mitochondrial lipolysis ability AMPK, the upstream negative regulator of ACC, also shows some anti-senescence activity.

Lipid metabolism depends heavily on AMPK. AMPK enhances lipolysis by upregulating ATGL expression AMPK can also suppress lipid production by inhibiting ACC activation by phosphorylating ACC1 Ser 79 Ala and ACC2 Ser Ala 92 and downregulating SREBP1c expression 93 , AMPK affects organism senescence directly or indirectly in a variety of ways.

For example, dietary restrictions delay the senescence of many species, in which AMPK is widely involved. elegans , AMPK and dietary restriction increase FAO through mitochondrial-peroxisome coordination, thereby maintaining homeostasis and plasticity within the mitochondrial network to extend life Greer et al.

elegans was mediated through the AMPK-FoxO transcription factors pathway. AMPKα subunit AAK-2 is activated by either a mutation that reduces insulin-like signaling or an environmental stressor that increases the AMP:ATP ratio, which can extend lifespan in C.

elegans 97 , A similar situation exists in mice. For instance, the pharmacological stimulation of AMPK can imitate caloric restriction induced comparable gene expression patterns and provide extensive protection against age-related diseases Fibroblast growth factor 21 can exhibit anti-senescence effects by elevating the expression of AMPK, which regulates lipid and glucose metabolic balance , blocking the p53 signaling pathway in an AMPK-dependent manner As an AMPK agonist, metformin plays a dual role in cancer prevention and anti-senescence , Inhibiting mTOR signaling plays a crucial role in mammalian senescence by reducing the accumulation of protein toxicity and oxidative stress 99 , increasing autophagy to clear damaged proteins and organelles , and enhancing the self-renewal capacity of hematopoietic stem cells and intestinal stem cells Ketone bodies are endogenous metabolites produced by the liver from fatty acids and ketogenic amino acids when glucose availability is low, such as during fasting, caloric restriction, or prolonged exercise Ketone bodies can be used as an alternative fuel source by many tissues, especially the brain, heart, and skeletal muscle, when glucose is scarce or absent These bodies can also cross the blood—brain barrier and supply energy to the central nervous system.

Ketone bodies are scary to clinicians because of the high mortality rate of ketoacidosis; however, in reality, the ketone bodies have signaling functions that regulate inflammation, epigenetics, oxidative stress, and other cellular processes by binding to specific receptors and enzymes — The bodies may also modulate gene expression and protein synthesis.

Ketone bodies are linked to multiple mechanisms of senescence and resilience, such as glucose sparing, mitochondrial biogenesis, autophagy, and hormesis — ; thus, they have anti-cancer, anti-angiogenic, and anti-atherogenic effects. Ketone bodies also reduce neuroinflammation and β-amyloid and tau accumulation, and improve memory and healthy lifespan in a senescent mouse model The most well-known ketone body, 3-hydroxybutyrate 3-OHB , binds to specific hydroxycarboxylic acid receptors to inhibit histone deacetylases, free fatty acid receptors, and nucleotide oligomerization domain NOD -like receptor protein 3 inflammasomes.

This initially inhibits lipolysis, inflammation, oxidative stress, cancer growth, angiogenesis, and atherosclerosis, and may increase lifespan associated with exercise and caloric restriction Additionally, 3-OHB protects muscle proteins from damage caused by systemic inflammation and is a crucial part of the metabolic defense against insulin-induced hypoglycemia Phospholipids are major components of biological membranes and consist of a glycerol backbone, two fatty acid chains, and a polar head group.

Phospholipids are essential for membrane structure, fluidity, and function, as well as for intracellular signaling, trafficking, and metabolism Phospholipids are synthesized in different cellular compartments by various enzymes and transported by specific carriers or vesicles.

Phospholipids mainly include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, and cardiolipin.

Phospholipids can also be degraded or modified by phospholipases, acyltransferases, and other enzymes that regulate their turnover and diversity Phospholipids play important roles in senescence and age-related diseases. Senescence is associated with changes in phospholipid composition, metabolism, and transport in different tissues and organs.

These changes may affect membrane integrity, fluidity, and function, as well as cellular signaling and homeostasis , For example, senescence leads to decreased unsaturated fatty acid levels and increased saturated fatty acid levels in phospholipids, which may impair membrane fluidity and increase oxidative stress Senescence also alters the levels of specific phospholipid species, such as phosphatidylcholine, phosphatidylethanolamine, and cardiolipin, which may affect mitochondrial function and biogenesis Phospholipid interventions may have beneficial effects on senescence and lifespan.

Dietary supplementation or genetic manipulation of phospholipids or their precursors can modulate membrane properties, cellular signaling, and mitochondrial function in various model organisms.

For instance, phosphatidylcholine or choline supplementation improved cognitive function and memory in aged rodents Overexpression of cardiolipin synthase or supplementation of cardiolipin precursors can enhance mitochondrial function and extend lifespan in yeast, worms, flies, and mice Sphingolipids are a diverse class of lipids that are involved in various cellular processes such as membrane structure, signal transduction, cell cycle regulation, apoptosis, senescence, and inflammation Sphingolipids are synthesized de novo in the endoplasmic reticulum from non-sphingolipid precursors, such as serine and palmitoyl-CoA, and then further modified in the Golgi apparatus and other organelles to generate a variety of complex sphingolipids with different polar head groups The major bioactive sphingolipids include ceramide Cer , sphingosine, sphingosinephosphate S1P , and ceramidephosphate, which can act as second messengers or ligands for specific receptors to modulate cellular responses Sphingolipids have been implicated in the regulation of senescence and age-related diseases, as they can affect several hallmarks of senescence such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication In general, Cer and its derivatives induce cellular senescence and promote senescence phenotypes, while S1P and its receptor signaling delay senescence and extend lifespan For example, sphingolipids are involved in sarcopenia, an age-related disorder of loss of skeletal muscle mass and function.

Park et al. In addition, SPT deletion or myriocin treatment enhances mitochondrial function, autophagy, and proteostasis in aged muscle cells, suggesting that sphingolipids may impair these processes by affecting endoplasmic reticulum stress and calcium homeostasis.

Sterols are essential components of eukaryotic cell membranes, where they regulate membrane fluidity, permeability, and microdomain formation. Sterols also have important roles in animal physiology, as they are precursors of steroid hormones such as glucocorticoids, mineralocorticoids, androgens, estrogens, and progestins, which modulate various metabolic, reproductive, and immune functions Sterols are synthesized from acetyl-CoA through a complex pathway that involves more than 20 enzymes and intermediates The first steps of sterol biosynthesis occur in the cytosol and endoplasmic reticulum, where acetyl-CoA is converted to mevalonate by three enzymes: acetoacetyl-CoA thiolase, HMG-CoA synthase, and HMG-CoA reductase.

Mevalonate is then converted to isopentenyl pyrophosphate IPP and dimethylallyl pyrophosphate DMAPP , which are the building blocks of isoprenoids.

IPP and DMAPP are used to synthesize geranyl pyrophosphate, farnesyl pyrophosphate, and squalene, which are the precursors of sterols and other isoprenoids such as ubiquinone, dolichol, and prenylated proteins The final steps of sterol biosynthesis involve the cyclization of squalene to form lanosterol, which is then converted to cholesterol by a series of modifications such as hydroxylation, demethylation, reduction, and isomerization.

Take cholesterol, the predominant sterol in animals, for example, which is integral and indispensable to neuronal physiology during both development and adulthood.

As a major component of cell membranes and a precursor to steroid hormones, it helps regulate ion permeability, cell shape, intercellular interactions, and transmembrane signaling. Inherited diseases with mutations in cholesterol-related genes lead to impaired brain function. In these cases, brain cholesterol defects may be secondary to pathogenic factors and lead to functional deficits through altered synaptic function.

The Warburg effect reveals that tumor cells prefer ATP production by glycolysis over oxidative phosphorylation even in the presence of abundant oxygen The Warburg effect plays an important role in the inhibition of cellular senescence and tumor promotion Glycolysis is upregulated in most senescence phenotypes.

Glycolytic gene overexpression promotes altered cancer metabolism in a variety of tumor cells. LDHA, involved in the conversion of pyruvate to lactate, was significantly increased in radiotherapy-induced senescent HCT and MDA-MB cells , Lactate liberation acidulates the extracellular environment involved in SRSPs Lactic acid-induced acidic intracellular pH activates Snail to promote epithelial-mesenchymal transition.

Increased Snail expression facilitated lung cancer cells to escape oncogene-induced senescence by directly suppressing p16 INK4a expression In this way, LDHA expression in senescent fibroblasts promotes PC3 cell invasion in the co-culture of senescent fibroblasts and PC3 cells Pharmacological inhibition of LDHA induces tumor cell senescence by suppressing heat shock response Beyond radiotherapy- and chemotherapy-induced senescent cancer cells, glycolysis is also activated in non-neoplastic senescent cells.

The levels of intermediate metabolites of glycolysis, including 3-phosphoglycerate, glucose 6-phosphate, fructose 6-phosphate, and phosphoenolpyruvate, are significantly increased in senescent fibroblasts, which highlights increased glycolytic flux to promote pyruvate and lactate production Senescent spermatogonial stem cells exhibit JNK phosphorylation and enhanced glycolytic capacity compared with young cells Senescence fibroblasts exhibit a significant increase in glucose consumption Increased glycolysis appears to be mediated by the overexpression of multiple glycolytic enzymes in distinct kinds of induced senescence.

First, GLUT proteins are encoded by SLC2. GLUTs 1—4 have widely established roles as glucose transporters GLUT1 is overexpressed in aged lungs and regulates fibrogenesis In this way, hyperglycemia-induced GLUT1 overexpression activates the mTOR pathway to increase P16 and P21 levels while promoting macrophage establishment of the SRSP response Second, HKs catalyze the phosphorylation of glucose as the first rate-limiting step in glycolysis HK1 and HK2 isozymes are highly expressed in replicative senescence human fibroblasts Third, PK, the rate-limiting enzyme in the final step of glycolysis, catalyzes pyruvate production.

The levels of this enzyme are upregulated in replicative senescence fibroblasts due to increased TCA activity and oxygen consumption In conclusion, glycolysis is increased in replicative senescent cells, but the regulatory mechanism of elevated enzyme expression and activity needs to be further characterized.

Tumor cells maintain cell proliferation by activating glycolysis to provide energy and precursors. Pyruvate, a glycolytic terminal product, enters the TCA cycle to produce metabolic intermediates that inhibit cellular senescence Citrate is the product catalyzed by citrate synthase in the initiation of the TCA cycle.

Recently, citrate has been reported to extend lifespan through mTOR and AMPK. However, citrate treatment results in cellular senescence and inhibits the proliferation of MCF-7 and HCT cancer cells Mechanistically, DNA damage pathways coupled with MAPK and mTOR pathways lead to citrate-induced cellular senescence αKG, a metabolite catalyzed by isocitrate dehydrogenase IDH , extends the lifespan of C.

elegans 23 , Drosophila , and mice 22 ; attenuates mouse age-related bone loss 24 ; and delays age-related fertility decline in mammals Sustaining this biological activity requires a continuous supply of ATP from mitochondria; however, the partial inhibition of the electron transport chain by αKG reportedly extends the lifespan of C.

elegans and mammalian cells Mechanistically, αKG inhibits intracellular senescence by regulating the expression of histone epigenetic modifications of BMP signaling proteins In addition, αKG prolongs Drosophila lifespan by activating AMPK and inhibiting mTOR The IDH1 RH mutant indirectly promotes senescence of malignant glioma cells by reducing αKG production Abnormal glucose metabolism in cancer cells activates arrested cellular senescence.

Cancer cells not only show active glycolysis for sufficient energy but also precursors from the pentose phosphate pathway PPP for intracellular biosynthesis G6PD-mediated oxidative PPP oxPPP provides NADPH to counteract oxidative stress, while non-oxPPP generates ribosephosphate R5P to provide precursors for nucleotide synthesis G6PD, a unique rate-limiting enzyme in the PPP, is involved in counteracting cellular senescence.

Mechanistically, G6PD knockdown increases the levels of P21, a classical marker of senescence, which promotes HCC and HCT cell senescence In addition, TAp73 enhances cell cycle inhibitory protein P21 by regulating metabolism TAp73 directly activates G6PD to increase PPP flow to inhibit cancer cell senescence Thus, G6PD may mediate, at least in part, the regulation of the senescence phenotype of cancer cells by TAp G6PD also regulates cellular senescence by affecting telomerase activity , G6PD-deficient fibroblasts exhibit delayed growth and accelerated senescence.

Ectopic expression of the human telomerase reverse transcriptase hTERT activated telomerase activity to prevent cellular senescence in G6PD-deficient fibroblasts Thus, the knockdown of hTERT significantly reduces G6PD expression and telomerase activity to promote cancer cell senescence Pharmacological inhibition of 6PGD induces cellular senescence and MCF-7 cell cycle arrest Non-oxPPP also regulates cellular senescence.

Supplementation of ribose 5-phosphate in drug-induced senescent human dermal fibroblasts significantly inhibited cell enlargement, a morphological alteration of cellular senescence In addition, hTERT knockdown inhibited the expression and activity of transketolase, a key enzyme of non-oxppp; increased cancer cell senescence; and reduced tumor burden in a mouse model of heterotypic xenograft SRSPs describe the diverse array of proinflammatory and profibrotic factors secreted by senescent cells SRSPs include cytokines, chemokines, growth factors, proteases, and extracellular matrix components that can affect the surrounding tissue microenvironment and modulate various biological processes, including inflammation, immunity, tissue remodeling, and tumorigenesis SRSPs are considered crucial drivers of chronic inflammation and senescence phenotypes, as they accumulate throughout normal senescence and in age-related diseases.

SRSPs can have both beneficial and detrimental effects on the organism, depending on the expression context and duration. While SRSPs can promote wound healing, tissue repair, and immune surveillance by stimulating cell proliferation, angiogenesis, and immune cell recruitment , they can also induce cellular senescence in neighboring cells, disrupt tissue homeostasis and function, and facilitate the development and progression of age-related diseases such as cancer, neurodegeneration, cardiovascular disease, diabetes, and osteoporosis , Growing evidence has shown that lipid metabolism and SRSPs are interconnected at multiple levels.

Conversely, some SRSP factors, such as IL-1β, IL-6, IL-8, and TNF-α, can affect lipid metabolism by altering lipogenic enzymes e. Disturbances in glucose metabolism can also induce cellular senescence and SRSPs in various tissues, such as pancreatic beta cells, endothelial cells, neurons, astrocytes, myocytes, and adipocytes — Conversely, SRSPs can modulate its metabolic activity by altering the expression and activity of key metabolic enzymes and transcription factors such as AMPK , PGC-1α, sirtuin 1 , FoxO , NF-κB , and nuclear factor erythroid 2-related factor 2 These factors can regulate various aspects of glucose metabolism such as glycolysis, gluconeogenesis, glycogen synthesis and breakdown, pentose phosphate pathway, and the hexosamine biosynthetic pathway.

SRSPs can also impair glucose uptake and utilization in these tissues by interfering with insulin signaling and inducing insulin resistance Apoptosis and autophagy are two major forms of programmed cell death that play important roles in senescence and age-related diseases.

Apoptosis is a regulated process of cell elimination that involves the activation of caspases, cleavage of cellular substrates, and formation of apoptotic bodies that are phagocytosed by macrophages or neighboring cells Autophagy is a catabolic process of self-digestion that involves the formation of double-membrane vesicles called autophagosomes, which engulf cytoplasmic components and deliver them to lysosomes for degradation Both apoptosis and autophagy are essential for maintaining cellular homeostasis, tissue integrity, and organismal health, as they remove damaged or redundant cells and organelles, recycle nutrients, and regulate inflammation and immunity However, both processes also decline with senescence, leading to the accumulation of dysfunctional cells and organelles, oxidative stress, chronic inflammation, and impaired tissue repair and regeneration The relationship between apoptosis and autophagy in senescence is complex and context-dependent.

On the one hand, apoptosis and autophagy can cooperate or compensate for each other to maintain cellular quality control and prevent senescence or tumorigenesis.

For example, autophagy can remove damaged mitochondria that produce ROS and trigger apoptosis Autophagy can also degrade pro-apoptotic factors or inhibit apoptotic signaling pathways, thus protecting cells from excessive or inappropriate cell death.

On the other hand, apoptosis and autophagy can antagonize or compete to modulate cellular fate and function. For instance, apoptosis can inhibit autophagy by cleaving autophagy-related proteins or blocking autophagosome-lysosome fusion. Apoptosis can also induce autophagy as a survival mechanism or a secondary mode of cell death when caspase activation is impaired or overwhelmed The balance between apoptosis and autophagy in senescence is influenced by various factors, including genetic background, environmental stimuli, hormonal status, metabolic state, and disease conditions.

Lipid and glucose metabolism are the two main pathways that provide energy and substrates for cellular function and survival. Dysregulation of lipid or glucose metabolism can affect the balance between apoptosis and autophagy. Lipid metabolism is regulated by various factors, including hormones, nutrients, and oxygen levels.

Lipid metabolism can modulate apoptosis and autophagy by affecting the production of ROS, activation of signaling pathways, and formation of lipid droplets or membrane structures For example, excessive lipid accumulation can induce oxidative stress and ER stress, which can trigger apoptosis or autophagy by activating the JNK, p53, or PKR-like endoplasmic reticulum kinase PERK pathways — Conversely, lipid depletion can also induce apoptosis or autophagy by impairing mitochondrial function, reducing ATP levels, or activating the AMPK pathway , Moreover, lipid metabolism can influence autophagic membrane initiation and elongation by providing phospholipids or fatty acids as precursors or modulators Lipid metabolism can be regulated by autophagy through the degradation of lipid droplets or lipogenic enzymes in a process called lipophagy Similarly, glucose metabolism can regulate apoptosis and autophagy by affecting the production of ROS, activation of signaling pathways, and maintenance of energy homeostasis.

For example, high glucose levels can induce oxidative stress and ER stress, which can trigger apoptosis or autophagy by activating the p38 MAPK, NF-κB, or CHOP pathways — Conversely, low glucose levels can also induce apoptosis or autophagy by impairing mitochondrial function, reducing ATP levels, or activating the AMPK pathway Moreover, glucose metabolism can influence autophagy induction and progression by providing hexosamines or acetyl-CoA as regulators , Furthermore, glucose metabolism can be regulated by autophagy through the degradation of glycogen granules or glycolytic enzymes in a process called glycophagy The relationship between insulin signaling and glucose and lipid metabolism is essential for maintaining energy homeostasis and preventing metabolic diseases.

Insulin also stimulates lipid synthesis and storage by activating the same pathway and downstream targets such as SREBPs, ACC, and FAS Insulin also inhibits glucose production by suppressing the expression and activity of enzymes involved in gluconeogenesis, such as phosphoenolpyruvate carboxykinase PEPCK and glucosephosphatase G6Pase , or lipolysis, such as HSL and ATGL However, insulin signaling and glucose and lipid metabolism can be disrupted by various factors such as obesity, inflammation, oxidative stress, endoplasmic reticulum stress, and senescence.

These factors can impair insulin action and induce insulin resistance by interfering with insulin receptor function or downstream signaling components. For instance, oxidative stress can reduce insulin receptor tyrosine phosphorylation and Akt activation by increasing the activity of protein tyrosine phosphatase 1B or protein kinase C PKC Mitochondrial dysfunction can impair lipid oxidation and increase lipid accumulation in non-adipose tissues such as skeletal muscle or liver, which can cause lipotoxicity and impair insulin action by activating PKC, JNK, or IKKβ Endoplasmic reticulum stress can also induce insulin resistance by activating the unfolded protein response UPR , which can suppress insulin receptor expression or activate JNK or PERK, which can phosphorylate IRS-1 on serine residues and inhibit its tyrosine phosphorylation Conversely, senescence can also affect insulin signaling and glucose and lipid metabolism by reducing the expression or activity of insulin receptors or their substrates, increasing the levels of inflammatory cytokines or oxidative stress markers, impairing mitochondrial function or autophagy, or altering the composition or function of gut microbiota.

Several transcription factors play pivotal roles in modulating insulin action and lipid homeostasis in response to senescence. FoxO factors can induce the expression of genes involved in gluconeogenesis such as PEPCK and G6Pase , or genes involved in FAO such as CPT1 or ACOX , thereby antagonizing the effects of insulin on glucose and lipid metabolism FoxO factors can also induce the expression of genes involved in antioxidant defense such as superoxide dismutase or catalase, or genes involved in anti-inflammatory responses, such as IL or suppressor of cytokine signaling 3, thereby protecting against oxidative stress and inflammation induced by senescence FoxO factors can also induce the expression of genes involved in autophagy, such as LC3 or Atg12 , thereby promoting the clearance of damaged organelles or proteins accumulated during senescence Glucose is one of the main sources of cellular energy.

Excessive glucose intake and abnormally elevated circulating blood glucose levels are associated with chronic diseases such as obesity and diabetes. On the one hand, the metabolic changes caused by hyperglycemia and diabetes promote cellular senescence, leading to tissue dysfunction and various complications such as diabetic retinopathy.

Pancreatic β-cells sense elevated blood glucose levels and secrete insulin correspondingly to maintain blood glucose levels within a narrow range. Glycolysis is increased in diabetic β-cells, which inhibits β-cell function A diabetic environment and SRSPs are considered drivers of diabetic retinopathy senescence in vitro and in vivo.

High glucose exposure accelerates cellular senescence However, glycolysis was significantly reduced rather than increased in an in vitro model of senescence. The presence of a negative feedback regulatory mechanism in an in vitro model may reduce levels of the glucose transport proteins GLUT1 and GLUT3 and the glycolytic enzyme PFKFB3, affecting the rate of glucose transport On the other hand, cellular senescence may also affect insulin secretion and sensitivity, thereby increasing the risk of developing diabetes.

Adipose precursor cells affect neighboring non-senescent cells through the secretion of SRSP factors such as activin A, IL-6, and TNFα, leading to impaired adipogenesis and reduced insulin sensitivity, which may also be involved in T2D progression Abnormal lipid accumulation during senescence is mainly caused by increased fatty acid uptake, de novo lipogenesis, and decreased FAO processes.

Mitochondrial integrity and autophagy induction are also diminished during senescence, leading to decreased lipolysis. These changes further impart lipotoxicity to the cell, depleting energy in the tissues and altering cellular signaling, thereby accelerating senescence and the early onset of age-related diseases Multiple adipogenesis enzymes are upregulated in senescent hepatocytes, including FAS, ACC, and stearoyl-CoA desaturase SCD In addition to lipid synthesis, excessive lipid intake increases FAO in the mitochondria and the ROS produced, leading to mitochondrial DNA damage and mitochondrial dysfunction Excessive lipid intake inhibits autophagy activation signaling and reduces autophagy levels.

Reduced autophagy levels lead to the accumulation of large amounts of waste products and toxins in the cell, interfering with cellular function and homeostasis and accelerating cellular senescence Excess saturated fatty acids activate the NF-κB and JNK signaling pathways by binding to Toll-like receptor 4 on the cell surface, thereby inducing the expression and release of inflammatory factors , Stress can impair glucose and lipid metabolism by altering the levels of insulin, leptin, cortisol, and other hormones that modulate appetite, energy expenditure, and glucose uptake Stress can also induce lipotoxicity, which is the accumulation of excess lipids and their metabolites in non-adipose tissues, such as the liver, muscle, heart, and brain Lipotoxicity can cause cellular damage, inflammation, insulin resistance, and apoptosis, leading to metabolic disorders and age-related diseases Moreover, stress can affect the mitochondrial function and autophagy of cells, which are involved in glucose and lipid metabolism Mitochondria are organelles that produce energy from glucose and fatty acids, while autophagy is the process that degrades damaged or excess cellular components, such as lipids.

Stress can induce mitochondrial stress, which is the imbalance between mitochondrial biogenesis and degradation, resulting in mitochondrial dysfunction, oxidative stress, and impaired energy metabolism Stress can also modulate autophagy, which can have both beneficial and detrimental effects on senescence depending on the stress type and duration.

Autophagy can enhance stress resistance and protein homeostasis by removing damaged mitochondria and lipids, but it can also promote cell death and inflammation by activating ferroptosis, a form of iron-dependent lipid peroxidation. Environmental pollution, especially air pollution, can expose the body to various harmful substances, such as particulate matter, ozone, nitrogen dioxide, and polycyclic aromatic hydrocarbons.

These substances can induce oxidative stress, inflammation, and endothelial dysfunction, which can impair glucose and lipid metabolism — Oxidative stress can damage DNA, proteins, and lipids, leading to cellular senescence and apoptosis Inflammation can alter the levels of cytokines, such as IL-6 and TNF-α, which can affect the secretion and action of insulin, a hormone that regulates glucose uptake Glucose and lipid metabolism are regulated by various hormones, enzymes, and signaling pathways that respond to temperature changes, such as thermogenesis, cold exposure, or heat stress , , Temperature can modulate glucose and lipid metabolism by altering the levels of adipokines, thyroid hormones, catecholamines, and other hormones that modulate energy balance, thermoregulation, and glucose uptake.

Temperature can also affect lipid lipolysis and oxidation, which are the processes that break down and utilize lipids for energy. Lipolysis is the hydrolysis of triglycerides into fatty acids and glycerol, while oxidation is the conversion of fatty acids into acetyl-CoA, which is used by the Krebs cycle.

Temperature can induce lipolysis and oxidation by activating HSL, ATGL, and CPT, which are enzymes that catalyze lipid breakdown and transport. Temperature can also affect the glycerolipid metabolism and signaling of cells, which are involved in glucose and lipid metabolism Therefore, temperature can influence senescence through multiple aspects of glucose and lipid metabolism that affect cellular health and function Figure 3.

Figure 3. Environmental factors influence senescence through glucose and lipid metabolism. Environmental factors such as excessive glucose intake, lipid overaccumulation, stress, environmental pollution, and temperature can promote cellular senescence by increasing glycolysis and inhibiting fatty acid oxidation.

POI is associated with metabolic disturbances, including glucose and lipid metabolism, which may increase the risk of long-term complications, such as cardiovascular diseases and osteoporosis Glucose metabolism is regulated by insulin. Estrogen, the main ovarian hormone, modulates insulin sensitivity and glucose homeostasis by influencing insulin secretion, signaling, and action in various tissues.

Estrogen deficiency in POI may impair glucose metabolism and lead to insulin resistance, hyperglycemia, or diabetes mellitus Estrogen also affects lipid metabolism by regulating the expression and activity of enzymes and receptors involved in lipid synthesis, transport, and degradation Zhou et al.

Moreover, they identified several metabolites related to glucose metabolism and lipid metabolism that were altered in patients with POI, including lactate, pyruvate, citrate, carnitine, acylcarnitine, glycerol, and glycerophospholipids.

In conclusion, POI affects not only ovarian function but also metabolic health. POI patients may have impaired glucose and lipid metabolism due to estrogen deficiency, which may increase their risks of developing metabolic disorders or cardiovascular diseases.

Therefore, it is important to monitor and manage the metabolic status of POI patients and provide appropriate hormonal replacement therapy or lifestyle interventions to prevent or reduce the adverse outcomes associated with POI.

Platelets are cell fragments without nuclei that participate in hemostasis and thrombosis. The levels of lipid peroxides in platelets increase during senescence. Lipid peroxidation is important for cell function. It causes extensive damage to cell membranes and subcellular granules, leading to enzyme inactivation and destruction, and inhibition of metabolic pathways and cell division.

The accumulation of lipid peroxidation products in aged platelets may cause cumulative damage to the membrane structure of platelets and their subcellular granules such as alpha granules, mitochondria, and the endoplasmic reticulum.

Lipid peroxidation may directly affect metabolic pathways by reducing the activity of lipid-dependent enzymes such as NADH- or succinate-cytochrome c reductase or indirectly by releasing lysosomal enzymes from alpha granules Platelets have a rich glycocalyx on their surface, and platelet glycosylation plays an important role in physiological hemostasis mechanisms, regulating platelet-receptor protein interactions, and dynamically remodeling surface glycosylation through their own glucose metabolism system.

Platelet glycosylation also participates in platelet senescence and clearance to regulate platelet count; meanwhile, platelet glycosylation abnormalities are closely related to primary immune thrombocytopenia, coronary heart disease, and related diseases, and are potential targets for anti-platelet therapy Down syndrome DS is a genetic disorder caused by an extra copy of chromosome 21, which results in cognitive impairment, physical abnormalities, and increased risks of age-related comorbidities.

Individuals with DS typically exhibit premature senescence phenomena, including skin senescence, graying hair, cataracts, osteoporosis, atherosclerosis, immune decline, and memory loss Likewise, the glucose and lipid metabolism of patients with DS also changes, mainly manifesting as reduced serum cholesterol levels, increased triglyceride levels, increased insulin resistance, abnormal glucose tolerance, etc.

These changes may be related to genetic abnormalities, oxidative stress, mitochondrial dysfunction, and other factors in these patients.

Moreover, many changes occur in the brain lipids of patients with DS, including a significant reduction in esterified polyunsaturated fatty acids, especially fatty acids esterified into phosphatidylinositol and phosphatidylserine.

Lipid and glucose metabolism are two essential metabolic pathways that provide energy and building blocks for cancer cells. Cancer cells reprogram their lipid and glucose metabolism to support their rapid growth, survival, invasion, and resistance to therapy.

Cancer cells also enhance their lipid uptake by expressing more lipoprotein receptors, such as low-density lipoprotein receptor LDLR and scavenger receptor class B type I SR-BI , and lipid transporters, such as fatty acid transport proteins and FABPs , Moreover, cancer cells can mobilize lipids from adipose tissue or surrounding stromal cells through lipolysis or lipophagy , Lipids can be stored in lipid droplets or oxidized through mitochondrial β-oxidation to generate ATP and acetyl-CoA, which can fuel the TCA cycle and oxidative phosphorylation.

In response to this feature, ongoing efforts aim to adapt lipid metabolism as an anti-cancer drug. Some approaches are used in preclinical models in vitro and in vivo , and some drugs have entered clinical trials. Inhibiting lipid biosynthesis enzymes, such as FAS TVB , ACC Soraphen A , and SCD A , can induce endoplasmic reticulum stress and activate the unfolded protein response, leading to cell cycle arrest, apoptosis, or senescence.

By blocking lipid uptake receptors like LDLR GW or SR-BI ML , less cholesterol and other lipids are available for membrane production and signaling.

This blocking can also impair mitochondrial beta-oxidation and increase the accumulation of toxic lipids, such as ceramide and ROS, by inhibiting the lipid oxidase CPT1 etomoxir Inhibition of COX-2 or LPA receptors, lipid signaling molecules, modulates various pathways involved in cancer cell proliferation, survival, migration, angiogenesis, and inflammation , Finally, cancer progression can also be inhibited by altering the biophysical properties fluidity, curvature, and permeability of the membrane bilayer through the localization and activity of membrane-associated proteins and receptors, as typified by statins that reduce cholesterol concentrations in the plasma membrane and affecting lipid raft clustering and displacement of receptors in non-raft domains The main pathway of glucose metabolism in cancer cells is aerobic glycolysis, also known as the Warburg effect This is a phenomenon in which cancer cells preferentially convert glucose into lactate, even in the presence of oxygen and functional mitochondria.

Aerobic glycolysis allows cancer cells to rapidly consume glucose and produce ATP while avoiding the production of ROS that can damage DNA and proteins. Moreover, aerobic glycolysis provides cancer cells with various metabolic intermediates that can be used for the synthesis of nucleotides, amino acids, and lipids To support aerobic glycolysis, cancer cells increase their glucose uptake by overexpressing GLUTs, especially GLUT1 Cancer cells also upregulate key glycolytic enzymes, such as HK2, phosphofructokinase 1, pyruvate kinase M2, and LDHA, which are often regulated by oncogenic signals, such as KRAS, MYC, and HIF1α However, aerobic glycolysis is not the only mode of glucose metabolism in cancer cells.

Some cancer cells can also use oxidative phosphorylation OXPHOS to generate ATP from glucose-derived pyruvate in the mitochondria. OXPHOS can be activated in cancer cells under conditions, such as hypoxia, nutrient deprivation, or drug resistance OXPHOS is more efficient than glycolysis in terms of ATP production per glucose molecule but also generates more ROS.

OXPHOS can also provide cancer cells with acetyl-CoA and NADH, which can modulate various signaling pathways, such as histone acetylation and sirtuin activity. To support OXPHOS, cancer cells can modulate their pyruvate metabolism by regulating the expression or activity of pyruvate dehydrogenase, pyruvate dehydrogenase kinase, or pyruvate carboxylase.

Cancer cells can also use alternative substrates for OXPHOS, such as glutamine, fatty acids, or ketone bodies Cellular senescence can occur in both normal and cancer cells and has complex dependence effects on cancer development and treatment. On the one hand, cellular senescence is a cancer suppressor mechanism that prevents the proliferation of damaged or malignant cells.

SRSPs secreted by senescent cells recruit and activate immune cells to remove senescent cells Some immune cells, such as T helper 1 cells, can also trigger cancer cell senescence by secreting inflammatory cytokines. In addition, cellular senescence enhances the expression of cancer-associated antigens and immunogenic molecules on cancer cells, making them more susceptible to recognition and clearance by T cells.

Thus, T cells are a key component of cancer immunotherapy On the other hand, cellular senescence can also adversely affect T cell immunity and cancer therapy. First, senescent cells accumulate in cancers and normal tissues, releasing SRSPs with pro-tumorigenic effects such as promoting angiogenesis, invasion, metastasis, and drug resistance.

Second, T cell senescence decreases their proliferation, cytokine production, and cytotoxicity and increases the expression of inhibitory receptors and pro-apoptotic molecules , Therefore, cellular senescence is a double-edged sword that can influence T cell immunity and cancer therapy in different ways.

Understanding the molecular mechanisms and interactions between how sugar and lipid metabolism regulate T cell senescence could provide new insights and strategies for improving anti-cancer therapy. T cell metabolism is tightly linked to T cell activation, differentiation, and function.

T cells undergo metabolic reprogramming upon antigen stimulation, switching from a quiescent state that relies on oxidative phosphorylation to a highly glycolytic state that supports rapid proliferation and effector functions However, chronic or excessive stimulation can lead to T cell exhaustion or senescence, which are associated with metabolic dysregulation, such as impaired glucose uptake, reduced glycolytic capacity, and altered mitochondrial function In addition to glucose metabolism, lipid metabolism plays a crucial role in regulating T cell immunity.

Senescent T cells have reduced FAO capacity and increased dependence on FAS. Targeting FAS with pharmacological inhibitors or gene knockdown induces apoptosis in senescent non-functional T cells and improves anti-cancer immunity.

Conversely, enhancing FAO with pharmacological activators or gene overexpression can prevent or reverse T cell senescence and exhaustion by restoring mitochondrial function and reducing oxidative stress The relationships between different types of lipid components, glucose metabolites, and senescence have been reported , However, an in-depth study of the regulatory relationships of the key enzymes is necessary to screen anti-senescence drugs.

New anti-cancer drugs may also be developed by targeting tumor cell senescence. Various aspects of glucose and lipid metabolism are closely related to senescence. In lipid metabolism, decreased fatty acid catabolism is directly related to senescence onset, including mitochondrial β-oxidation 34 , 36 , 37 , 57 , , peroxisomal β-oxidation 54 , 55 , α-oxidation 82 , 84 , and ω-oxidation The most prominent key enzymes include CPT1 and ACOX1.

Drugs such as fenofibrate can exert anti-senescence effects by targeting PPARα, the gene upstream of CPT1 and ACOX1 Figure 4. In addition to fatty acid catabolism and synthesis, acetyl coenzyme A undergoes a variety of pathways to ketone bodies, phospholipids, sphingolipids, and sterols, which perform a wide range of biological functions and exert pro- or anti-senescence effects Figure 5.

The effects of these lipids on senescence often depend on the amount, subtype, and state of the cellular microenvironment. Cer induces cellular senescence, whereas S1P, another sphingolipid component, delays senescence and extends lifespans , Figure 4.

Targeting critical enzymes of fatty acid synthesis and catabolism to delay senescence. Activation of CPT1 and ACOX1 directly or indirectly through the peroxisome proliferator-activated receptor α PPARα pathway promotes fatty acid oxidation, both of which may have a senescence-delaying effect.

AMPK also inhibits senescence by inhibiting the mTOR and NF-κB pathways. The gray arrows represent normal metabolic pathways. The green pointed and blunt red arrows represent activating and inhibiting effects, respectively.

Figure 5. Various metabolic products of fatty acids have rich biological functions and affect senescence. Multiple glucose metabolism pathways are involved in the regulation of intracellular senescence.

Several rate-limiting enzymes in glycolysis, including HK2 and PK, are highly expressed in senescent cells , Although the pharmacological activation of Nrf2 increases HK2 expression 18 , other mechanisms require further investigation.

Several key enzymes of the PPP, a branch of the glycolytic pathway, are also involved in the regulation of intracellular senescence. The key enzymes promote cellular senescence by upregulating P21, P16, and telomerase activity Notably, the dietary TCA-cycling metabolites citrate and αKG delay cellular senescence 23 — Therefore, supplementation of these metabolites may provide an effective intervention for the treatment of senescence-related dysfunction Figure 6.

Figure 6. Glucose metabolism is upregulated in senescent cells. Multiple enzymes of glycolysis are upregulated. For instance, lactate release mediated by monocarboxylate transporters MCTs is involved in senescence-related secretory phenotypes SRSPs.

Several metabolites in the tricarboxylic acid TCA cycle, including α-ketoglutarate αKG and citrate, delay senescence. Environmental factors can affect senescence through glucose and lipid metabolism, which are essential for energy production and cellular function.

Alterations in the external environment such as nutrition, stress, environment, pollution, and temperature accelerate cellular senescence by regulating glucose and lipid metabolism through a variety of hormones, enzymes, and signaling pathways.

Thus, targeting aberrant metabolism may delay normal cellular senescence. In summary, fatty acid and glucose metabolism are essential in the maintenance of normal cellular function, both of which are disturbed by senescence.

Conversely, disturbances in fatty acid and glucose metabolism can further lead to senescence. Two pathway-related enzymes and metabolites are involved in the regulation of cellular senescence. While many advances have been made in recent years, several important issues must still be addressed, including: a What are the initiating factors of senescence and metabolic disorders?

b While reports suggest a correlation between metabolic disorders and senescence, the true causal relationship remains undetermined. c Anti-senescence therapies proven to work in humans are scarce.

Understanding the role of enzymes and metabolites in fatty acid and glucose metabolism may provide answers for a more comprehensive understanding of senescence. BL and QM investigated and wrote the first draft of the manuscript.

XG and HS wrote sections of the manuscript. ZX and YW contributed to conception the study and acquire funds. HZ contributed to design of the study and acquire funds. BL, QM, XG, HS, ZX, YW, and HZ were involved in drafting, revising the manuscript, and agree to be accountable for the content of the work.

All authors contributed to the article and approved the submitted version. This work was supported by the National Natural Science Foundation of China Nos. We sincerely thank the reviewers and editors of Frontiers in Nutrition for providing valuable suggestions on this paper.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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