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Citation: Ikeda K and Yamada T UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes. Received: 20 March ; Accepted: 23 June ; Published: 28 July Copyright © Ikeda and Yamada.
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MINI REVIEW article Front. This article is part of the Research Topic Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity View all 16 articles. UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes. CD36 is necessary for transport of lipids via lipoproteins and FFA-bound albumin in BAT as well.
Clearance of both lipoproteins and FFAs from plasma and uptake into BAT were diminished in cold-exposed Cd36 KO mice Bartelt et al. CD36 is also required for uptake of lipid-related molecules into BAT, such as coenzyme Q CoQ Anderson et al.
CoQ contains an isoprenoid tail and is a necessary electron transporter between complexes in the electron transport chain.
Therefore, it is required for both ATP synthesis and heat production in BAT. High levels of CoQ are present in BAT despite low levels of endogenous synthesis, suggesting a requirement for uptake of CoQ from the circulation. Although CD36 is present in other tissues, these phenotypes were not reflected throughout the mice.
These studies highlight the requirement of CD36 for proper uptake of lipids and hydrophobic molecules into cold-activated BAT.
Lipoproteins are means of transporting lipids of varying polarity from centers of lipid processing, such as the intestine and liver, to peripheral tissues through the circulation. They are comprised of a phospholipid monolayer interlaced with apolipoproteins that serve as structural reinforcements and as LDL receptor LDLR recognition sites to aid in endocytosis.
Lipoproteins fall into four main classes depending on their relative composition of proteins and lipids: high density HDL , low-density LDL , very low-density VLDL , and chylomicrons. In addition to the characteristic structure of each class, different lipoproteins also serve different functions.
For example, LDL carries circulatory cholesterol and easily enters arterial walls, while chylomicrons are essential for dietary lipid transport to the liver and peripheral tissues. Nonetheless, each class has a vital role in lipid transport, endocytosis, and hydrolysis Zanoni et al.
LDL endocytosis begins with recognition at the cell membrane by a low-density lipoprotein receptor LDLR. Following recognition, a clathrin-coated pit forms a vesicle around the endocytosed lipoprotein.
The vesicle is directed to endosomes where a drop in pH causes release of LDL from LDLR. Acidic lipases in the newly formed lysosome hydrolyze the contents of LDL to release FAs from TGs and unesterified cholesterol from cholesteryl esters Figure 3.
Cholesterol is incorporated into cell membranes and negatively regulates its own synthesis by preventing translocation of sterol regulatory binding protein SREBP from the ER to the Golgi, thereby blocking transcriptional activation of HMG-CoA reductase Brown and Goldstein, FAs released from LDL are shuttled to the ER for synthesis into membrane lipids, the Golgi for protein acylation, and the mitochondria for FA β-oxidation.
Figure 3. Triglycerides are delivered to cold-activated BAT through LPL hydrolysis at the endothelial wall. Following β3-adrenergic receptor B 3 AR activation by norepinephrine NE signaling a drop in temperature, hepatocytes and enterocytes mobilize triglyceride TG -rich lipoproteins TRLs into the blood for transport to brown adipocytes.
Hydrolysis is dependent on the co-factor apolipoprotein C-II apoC-II and activator apolipoprotein A-V apoA-V. As hydrolysis occurs, TRLs reduce into intermediate lipoproteins IDLs , low-density lipoproteins LDL , and finally remnant particles to be cleared by the liver.
Each reduction in size is accompanied by a loss of triglycerides TGs. Imported FAs are funneled into mitochondrial β-oxidation and eventual heat production. In brown adipocytes, LDLR endocytosis fuels the electron pool needed for proton gradient uncoupling and heat production Figure 4.
LDLR is recycled back to the plasma membrane for addition rounds of endocytosis Ikonen, LDLRs are also necessary in systemic cholesterol and triglyceride balance during cold exposure.
In this model, the liver is unable to clear lipoprotein remnants produced from FA uptake in BAT following LPL-mediated TG hydrolysis and thus cholesterol remains in the circulation. Coordinated plasma lipid clearance between the liver and BAT during cold exposure requires proper protein-mediated lipid uptake, such as LDLR endocytosis.
Figure 4. Triglycerides and cholesterol are delivered to cold-activated BAT through LDLR mediated endocytosis. Low-density lipoprotein receptors LDLRs recognize apolipoprotein B on the surface of low-density lipoproteins LDL.
A clathrin-coated pit forms around the bound receptor and an endocytotic vesicle forms. An internal drop in pH prompts release of LDL from LDLR for hydrolysis in the lysosome. Acid hydrolases liberate fatty acids FAs from triglycerides TGs and cholesterol within LDL.
In brown adipocytes, FAs are shuttled into mitochondrial β-oxidation to fuel downstream heat production. Cholesterol is incorporated into cell membranes and signals a negative feedback loop of biosynthesis by preventing sterol-regulatory-element binding proteins SREBP translocation to the Golgi from the ER.
This prevents proteolytic processing and localization to the nucleus, thereby inhibiting expression of genes encoding cholesterol synthesis enzymes HMG-CoA reductase and lipoprotein receptors LDLR. TGs are the neutral storage form of FAs and travel between tissues through the bloodstream via chylomicrons and VLDL.
Chylomicrons are the largest form of lipoprotein and are assembled by the small intestine following emulsification of dietary fats.
TGs packaged into chylomicrons mainly enter adipose tissue and skeletal muscle due to high lipoprotein lipase LPL activity.
The remaining TG is taken up by the liver and can be repackaged into VLDL for use throughout the body. Alternatively, FAs are synthesized by the liver through de novo lipogenesis, assembled into TG, and mobilized in VLDL. As TGs are liberated from VLDL for use by peripheral tissues, smaller remnants of decreasing TG content are formed such as intermediate-density lipoproteins IDL and LDL.
Like chylomicrons, VLDL is utilized by tissues after lipolysis by LPL. LPL is the predominant lipase in tissues with high levels of exogenous lipid uptake, such as adipose tissue, heart, and skeletal muscle.
LPL is a dimeric enzyme localized to the vascular lumen where it hydrolyzes plasma TGs into glycerol and FAs for tissue uptake. TG-derived FA uptake into BAT is reliant on localized LPL activity, as injection of an LPL inhibitor tetrahydrolipstatin or treatment with heparin to release LPL from the vascular wall in mice prior to cold exposure almost completely abolished labeled TRL uptake into BAT.
Mice lacking GPIHBP1 have increased plasma TGs due to reduced tissue uptake Cushing et al. As circulating lipoprotein levels are highly modulated in response to metabolic state, such as fasting and cold exposure, tight regulation of LPL activity is required.
Besides localization, LPL is primarily regulated post-translationally by several extracellular proteins.
Angiopoietin-like proteins ANGPTL are the main class of LPL regulators. ANGPTLs are secreted into the lumen and directly interact with LPL, preventing its dimerization and inhibiting lipolysis Hegele, ANGPTL4 is the predominant isoform in brown adipose tissue.
In BAT, ANGPTL4 expression is induced during periods of nutrient deprivation fasting and suppressed when substantial nutrients are available or needed, such as postprandially or during cold exposure Singh et al.
In cold-activated WAT, ANGPTL4 is upregulated to shift away from fat storage and toward output of FAs to support thermogenesis. BAT-specific ANGPTL4 KO mice exhibit reduced plasma TGs in the fed and fasted state, accumulation of 3 H from labeled triolein in BAT, and increased expression of CD36 in BAT Cushing et al.
LPL expression was unchanged, but activity was significantly increased in BAT from ANGPTL4 KO mice. ANGPTL4 KO mice had higher rectal temperature over time during a 4-h cold exposure, likely due to enhanced LPL activity in BAT fueling FA uptake and β-oxidation.
In sum, these studies highlight the necessity of tight LPL regulation in BAT to modulate TG and FA uptake during metabolic stress, including cold exposure. It has been shown that BAT relies more heavily on LPL-based uptake of TG-derived FAs rather than particle endocytosis, but cold exposure significantly enhances the uptake of TGs through both methods Khedoe et al.
This was observed through tracing of 3 H-triolein and 14 C cholesteryl esters which allow measurement of TG uptake by lipolysis and lipoprotein uptake by endocytosis, respectively. While VLDL is overwhelmingly shuttled to BAT when activated by exposure to cold, transport of HDL to the liver is drastically increased Schaltenberg et al.
HDL balances cholesterol flux between peripheral tissues and is both synthesized and excreted by the liver. This hepatic processing is dependent on endothelial lipase EL. Following extended cold exposure 1 week , expression of the gene encoding EL, Lipg , was increased in murine BAT.
Cold exposure was also shown to enhance HDL clearance from plasma. EL is known to promote TRL uptake, much like LPL. While EL expression is induced in BAT after cold exposure, it was not required for proper thermogenic activation, nor did its loss affect thermogenic transcriptional programs such as those controlled by PPAR-γ.
The advent and expansion of mass spectrometry based lipidomics has broadened the field of circulating lipids, and several lipid classes have been shown to be increased in blood plasma with cold exposure including acylcarnitines, ceramides, 12,dihydroxy-9z-octadecenoic acid 12,diHOME , and fatty acid esters of hydroxy fatty acids FAHFAs.
Little is known about how theses lipids are transported across plasma membranes, what functional roles they serve in non-shivering thermogenesis, and in what complex structure they are mobilized in the circulation.
Acylcarnitines are fatty acids conjugated to a carnitine through esterification. At the cellular level, acylcarnitines function as intermediaries facilitating transport of FFAs into the mitochondria for β-oxidation.
Carnitine palmitoyltransferase 1 CPT1 is embedded on the outer-surface of the mitochondrial membrane and esterifies the fatty acid from an acyl-CoA to carnitine. This acylcarnitine can then diffuse into the porous outer mitochondrial member.
Acylcarnitine is then brought into the inner mitochondria by carnitine acylcarnitine transferase CACT and de-carnitylated by CPT2. Besides their cellular role for fatty acid transport, acylcarnitines are also found in the blood plasma.
Plasma acylcarnitines increase with chronic diseases such as type 2 diabetes, cardiovascular disease, and inborn errors of metabolism as well as in acute metabolic stresses such as fasting, exercise, and cold exposure Muoio et al.
The functional role of acylcarnitines in the plasma has been proposed to range from protection from toxicity to a distinct storage pool that can be pulled from during energy demanding conditions Muoio et al. In cold exposure, short chain, medium chain, and long chain acylcarnitines are increased in the plasma while carnitine levels decrease Simcox et al.
This cold induction of increased plasma acylcarnitines is mediated by β3-adrenergic receptor induced WAT lipolysis, since adipose tissue-specific ATGL knockout mice had no changes in acylcarnitine levels with β3-adrenergic receptor agonist treatment.
Once FFAs are released from the WAT, they are taken up into the liver, where they transcriptionally activate CPT1, CACT, and CPT2 through an HNF4α-mediated mechanism as well as serve as substrate for acylcarnitine production Simcox et al.
These liver-produced acylcarnitines are then taken up into the BAT, skeletal muscle, and heart. In the BAT, the acylcarnitines are catabolized as a fuel source for thermogenesis.
Beyond the liver, there are other potential sources for cold induced plasma acylcarnitines; while ablation of acylcarnitine production in the liver causes cold intolerance, it is not sufficient to completely block the rise in plasma acylcarnitines with cold exposure.
Recently it has been shown that the kidney may also contribute to the plasma acylcarnitine pool Jain et al. These studies collectively demonstrate that plasma acylcarnitines are produced through a multi-tissue processing, and that they function as a fuel source for cold-activated BAT.
Several questions remain in understanding the regulation and transport of plasma acylcarnitines including how they are transported through the plasma membrane in the liver and in the brown adipose tissue.
Studies in Xenopus oocytes have demonstrated that acylcarnitines require a transporter to cross the plasma membrane, and cDNA libraries from mouse liver have demonstrated that these unknown transporters are present in the liver Berardi et al.
SLC22a1 was recently identified as an acylcarnitine exporter in the liver, and knockout of SLC22a1 led to decreased short and medium chain acylcarnitines in plasma but had no impact on long chain acylcarnitine levels Kim et al. Moreover, there has been no identified BAT acylcarnitine transporter and SLC22a1 has low expression in brown adipocytes.
Plasma long chain acylcarnitines have been shown to travel bound to albumin, while short and medium chain acylcarnitines are unbound. Whether albumin bound acylcarnitines are the dominant form of acylcarnitine in the circulation during cold exposure is unknown.
Future work will be needed to understand their entry into brown adipocytes and the kinetics of their uptake compared to FFAs of the same acyl chain. Ceramides are a long chain sphingoid base conjugated to a fatty acid through an amide bond and are the precursor to all sphingolipids.
Ceramides are known to circulate during tissue dysfunction and metabolic disease in both mice and humans. Plasma ceramide levels have been shown to correlate with risk of diabetes and coronary artery disease in a species-specific manner across human cohorts Tippetts et al.
Reduction of plasma and WAT ceramides in mice via increased degradation ceramidase overexpression or inhibition of ceramide synthesis SPTLC2 KO ameliorated HFD-induced obesity, insulin resistance, and hepatic steatosis Xia et al. SPTLC2 KO in WAT also enhanced adipocyte browning and resulted in an increase in beige adipocyte differentiation Chaurasia et al.
This suggests that ceramides act as signals to increase lipid storage in WAT and inhibit the beige program.
Moreover, liver SPTLC2 expression is upregulated in response to SPTLC2 KO in WAT, suggesting a means of communication to balance tissue ceramide levels. Despite the wealth of literature on ceramide function in metabolic disease and its regulation of the adipocyte differentiation program, little is known about how ceramides control brown and beige adipocyte maintenance or their direct role in thermogenic metabolism.
We have observed significant increases in plasma ceramides following acute cold exposure, with computational assessment revealing that these plasma levels are regulated by the BAT and the kidney Jain et al. More work is needed to characterize how these plasma ceramides are regulated in acute cold exposure, what their functional role may be, and what complexes facilitate their transport in the plasma during cold exposure.
At ambient temperature, ceramides are known to be associated with lipoproteins primarily LDL and have been shown to transfer between cells via extracellular vesicles EVs Hammad et al. These vesicles act as carriers for intercellular signaling molecules during metabolic stress, and many ceramide species act as second messengers for key metabolic pathways including insulin sensing and cell growth.
For example, during fasting, white adipose tissue traffics EVs containing signaling molecules such as caveolin 1 and very long chain ceramides to neighboring endothelial cells and vice versa Crewe et al.
EVs are also produced by adipose-derived stem cells during beige adipocyte differentiation and were shown to be sufficient to differentiate these stem cells into beige adipocytes Jung et al.
Additionally, BAT has been shown to be a significant contributor of exosomes into the circulation Thomou et al. It is unknown whether export of these vesicles is upregulated or if ceramides are enriched in these vesicles during cold exposure. Moreover, there are no known plasma membrane transporters of ceramides.
Ceramides in cold exposure remain an exciting area of research with many outstanding questions, including the role of ceramides in thermogenic metabolism as well as the function of plasma ceramides compared to ceramides produced in brown and beige adipocytes.
Upon β3-adrenergic receptor activation, linoleic acid is oxidized by cytochrome P and soluble epoxide hydrolase to produce 12,diHOME. Beyond BAT, other tissues are known to produce 12,diHOME, including the skeletal muscle, and contribute to the circulating pool to regulate body weight, energy expenditure, insulin sensitivity, and plasma lipid levels Vasan et al.
The uptake of 12,diHOME into brown adipocytes is regulated by CD36 and FATP1, and treatment of brown adipocytes with 12,diHOME is sufficient to increase translocation of CD36 and FATP1 Lynes et al. Further studies are needed to understand how 12,diHOME regulates mitochondrial oxidation, determine the mechanism of secretion from cells, and understand how this lipid circulates in the plasma.
FAHFAs are a recently discovered class of signaling lipids that regulate brown and beige adipocyte differentiation and maintenance.
Structurally, FAHFAs are fatty acids complexed to a hydroxy fatty acid through an ester bond Yore et al. There are numerous types of FAHFAs named for the acyl chains and the location of the hydroxylation including stearic-acidhydroxy stearic acid 9-SAHSA , oleic-acidhydroxy stearic acid 9-OAHSA , and palmitic-acidhydroxy stearic acids 9-PAHSA.
Both 5- and 9- PAHSA have been shown to increase brown adipocyte differentiation, insulin sensitivity, decrease inflammation in adipose tissue, and improve whole body glucose tolerance. Treatment of 3T3-L1 adipocytes or leptin deficient mouse models with 9-PAHSA led to increased expression of thermogenic genes including UCP1 Wang et al.
Part of this signaling is mediated through binding and activating G-protein coupled receptor GRP , and knockdown of GPR in 3T3-L1 cells abrogated the effect of 9-PASHA treatment Oh et al. Cold exposure induced the production of 5- and 9-PAHSA from WAT, with this production being mediated by lipolysis from triglycerides since knockout of ATGL led to ablated the cold-induced production Paluchova et al.
Many outstanding questions remain on how various species of FAHFAs impact brown and beige adipocytes and how they are transported into cells.
The numerous plasma lipids that act upon BAT is still an open area of study. For the purpose of this review, we have chosen to focus on plasma lipids that are transported into brown adipocytes, however there are a number of other lipids that are altered in brown adipocytes themselves that regulate thermogenesis.
These include ether lipids such as plasmalogens and cardiolipins Lynes et al. Although FFAs produced in the BAT are not necessary for thermogenesis Schreiber et al.
Interestingly, ether lipids have recently been observed to increase with cold exposure in studies where mice were acclimated to thermoneutrality then placed for 24 h in thermoneutrality, room temperature 22°C , and cold exposure 5°C as well as fasted for the final 5 h of temperature stress Pernes et al.
More work is needed to understand these various lipids in the plasma and how their transport is regulated. BAT is an important regulator of whole-body glucose and lipid homeostasis. Cold exposure increases the uptake of lipids into the BAT by fold and, in models of hyperlipidemia, can normalize plasma triacyclglycerol and cholesterol levels Bartelt et al.
Not only are thermogenic adipocytes able to regulate systemic lipid metabolism, but they are also reliant on the plasma lipid pool for fuel availability.
The importance of peripheral lipid storage for non-shivering thermogenesis has now been established through use of the ATGL KO studies and DGAT1 and 2 double KO studies Schreiber et al.
The uptake of these lipids into BAT from the circulation is dependent upon facilitated transport through dedicated protein transporters, chaperones, and endocytosis. This review focused on known mechanisms of lipid uptake into BAT, beginning with FFA uptake which is regulated in three distinct steps: CD36 and FATPs regulating 1 adsorption and 2 translocation, while FABP facilitates 3 desorption Hamilton, ; Chmurzyńska, Loss of CD36, FATP or FABP led to cold intolerance and an inability for cold exposure to regulate circulating FFA levels.
TGs and cholesterol can also be imported into BAT through LDL endocytosis, or for TGs, through LPL mediated lipolysis from TRL. While the majority of work has focused on uptake of FFAs, TGs, and cholesterol into BAT, questions remain on the import mechanisms that regulate other plasma lipids during cold exposure.
Recent work on plasma acylcarnitines has shown that they are taken up by BAT and are necessary for thermogenic capacity Simcox et al. Other work has shown that lipid containing exosomes are increased in the plasma with cold exposure and reflect brown adipocyte activity Chen et al.
More work is needed to understand how these lipids and lipid-containing vesicles are trafficked into cells, and to determine the tissues where these various plasma lipids are produced.
One existing challenge in the modeling of lipid uptake into brown adipocytes is standardization of protocols for cold exposure and mouse models.
Many studies have a range in cold exposure from 3 h to 1 week. Longer cold exposure, such as 72 h to 1 week, is associated with beige adipocyte differentiation, increased BAT mass, and increased food intake Ikeda et al. The variations in cold exposure timing and added variable of fasting during a traditional cold tolerance test make comparison difficult due to differences in thermogenic capacity and contribution of the beige depot.
Moreover, variations in housing temperature also impact the brown and beige adipocyte population and alter body weight in response to shifts in energy expenditure Fischer et al. Many of the studies associated with lipid uptake in brown adipocytes focus on 1 week including characterization of FABP and FATP.
Standardization would enable an understanding of the impact of BAT on the circulating lipid pool. Another barrier for lipid transport in thermogenic adipocytes is depot-specific gene modulation. Many mouse models for lipid transport assessed the function in BAT using ablation of the gene in all adipose tissue with cre expression driven by the adiponectin promoter or in whole body KO models.
All of the work to assess FATP1 function in BAT was performed in FATP1 null mice, as were several of the seminal studies on CD36 Lobo et al.
Models that use cre drivers target both the brown and beige adipocytes using UCP1-cre for genetic modulation of various genes. An important step in furthering our understanding of lipid transport in thermogenesis will be the development of mouse models that target only the brown or beige adipocytes.
Single cell sequencing has uncovered numerous unique markers of beige vs. brown adipocytes, while also identifying numerous sub-populations of adipocytes in brown and beige depots Merrick et al.
These challenges are particularly important since the uptake of lipids into each of these cell types may be mediated by distinct membrane composition and expression of transporters. Finally, although the majority of this review focused on lipids being transported into BAT for catabolism, lipids are capable of playing a number of signaling roles that regulate thermogenic potential.
Recent work by the Seale group has demonstrated that FA oxidation is an important mediator of beige adipocyte differentiation driven by transcriptional regulator PRDM The breakdown of these FAs into ketone bodies was necessary and sufficient to induce differentiation of pre-adipocytes into beige adipocyte Wang et al.
Beige adipocyte differentiation was also shown to be regulated by ceramide signaling which inhibits the beige program while promoting lipid accumulation needed for white adipocytes Chaurasia et al.
More work is needed to understand how lipids influence metabolism in brown and beige adipocytes and how they contribute to the thermogenic potential, as well as how these signals are mediated by transport into the BAT.
Lipid import from the circulation into brown adipocytes is necessary for thermogenesis. Once in the brown and beige adipocytes, these lipids can be catabolized as an energy source or serve as signaling molecules.
While there are fairly established mechanisms and function for FFA and TG uptake into BAT, more work is needed to characterize the uptake, circulating form, and functional role in thermogenesis for other lipids such as acylcarnitines, ceramides, and FAHFAs. The continued exploration and development of new technology to probe lipid uptake in brown and beige adipocytes will enable distinction of catabolism, storage, and signaling capabilities.
Lipid transport proteins are essential to proper systemic lipid metabolism, and tight regulation of this transport is necessary to prevent disease. GW, AM, and JS contributed to the conception, writing, literature searches, and first draft of the manuscript.
GW created the figures for the manuscript. JN and JS contributed editing, revisions, literature searches, and final draft overview. All authors contributed to manuscript revisions, read, and approved the submitted version.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was also supported in part by startup funds from the University of Wisconsin-Madison School Department of Biochemistry to JS and NIH RO1 DK to JN.
Other funds that supported this publication include funds from the Diabetes Research Center at Washington University in St. Louis of the National Institutes of Health under award number P30DK 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.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. The authors would like to thank members of the Simcox laboratory including Helaina Von Bank, Raghav Jain, Paula Gonzalez, and Edrees Rashan as well as Jessica Davidson and Dr.
Alan Attie who helped in revising, editing, and offering feedback. Figures were made with BioRender. Abumrad, N. Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm.
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Overexpression of membrane-associated fatty acid binding protein FABPpm in vivo increases fatty acid sarcolemmal transport and metabolism. However, although UCP1 gene expression was detected at day 5, UCP1 protein levels were detected starting at day 10 and were maintained throughout differentiation Supplemental Figure 1F.
This pattern is similar to what was observed in mouse brown adipocyte cell culture models 3 , 47 where UCP1 gene expression precedes protein expression. Mitochondrial biogenesis during differentiation was monitored by examining the expression of the mitochondrial DNA—encoded mtDNA-encoded gene cytochrome c oxidase subunit 2 MT-CO2 and the protein expression of the translocase of the outer membrane TOM Moreover, compared with preadipocytes, transcription and translation levels of FABP4 , ADIPOQ , and CEBPA , markers of later-phase differentiation, were substantially higher in mature, differentiated adipocytes Figure 1C and Supplemental Figure 1G.
A Representative microscopic pictures of the morphology of undifferentiated and differentiated adipocytes. B Oil Red O staining of differentiated human primary adipocytes at passage number 10 P10 and 15 P C Protein expression of FABP4, adiponectin, and UCP1 at P10 and P15 in pre- and mature adipocytes.
D Immunofluorescence of differentiated adipocytes staining for mitochondria MitoTracker, red , lipid droplets LipidTOX, green , anti-UCP1 white , and nuclei DAPI, blue.
Scale bars: μm for all images except the higher magnification, which is 50 μm. E and F The mRNA expression profiles of β-ARs E and thermogenic related genes F in transfected siRNA-control siRNA-Ctrl and siRNA- ADRB3 adipocytes after 48 hours of transfection.
G UCP1 protein levels in transfected adipocytes after 48 hours and 72 hours of transfection. H Immunofluorescence of siRNA-Ctrl and siRNA- ADRB3 adipocytes stained with MitoTracker red , LipidTOX green , anti-UCP1 white , and DAPI blue.
Scale bars: μm. I Quantification of UCP1-positive adipocytes in siRNA-Ctrl and siRNA- ADRB3 adipocytes from 5 sections. Arrows indicate cells expressing UCP1. J — M Expression levels of mtDNA-encoded gene J , fatty acid oxidation genes K , fatty acid synthesis genes L , and creatinine kinase genes M in transfected siRNA-Ctrl and siRNA- ADRB3 adipocytes.
Gene expression data are normalized to siRNA-Ctrl adipocytes and expressed as mean ± SEM expression on a log 10 scale. mRNA levels for genes involved in fatty acid oxidation, namely CPT1 and citrate synthase CS , were also higher in mature adipocytes Supplemental Figure 1I.
The expression of all 3 β-ARs was detected in preadipocytes, and expression levels increased , , and 5-fold in mature adipocytes for ADRB1 , ADRB2 , and ADRB3 , respectively Supplemental Figure 1J. Staining with MitoTracker dye revealed an abundance of mitochondria in differentiated cells expressing UCP1, providing evidence for colocalization of UCP1 to the mitochondria Figure 1D and Supplemental Figure 2A.
In summary, the differentiated primary adipocytes from the SCLV region have the molecular machinery to support both lipolysis and thermogenesis. The adipocytes preserved the physiological properties that characterize their tissue of origin with high fidelity Loss of β 3 -ARs in differentiated primary SCLV adipocytes alters the cellular thermogenic machinery.
The reduction in both β 3 -AR and β 1 -AR transcripts suggests either some degree of off-target binding by the siRNA- ADRB3 or a physiological response by the cells as a consequence of reduced ADRB3 mRNA or protein.
To get a fuller picture of the effects of the specific silencing of ADRB3 , we assessed the effects of targeting ADRB1 with siRNA, which we report later in the manuscript. As observed during the differentiation of these adipocytes, lower UCP1 mRNA levels at 48 hours preceded the reduction in UCP1 protein, which was more evident by 72 hours Figure 1G.
Absence of UCP1 is known to alter mitochondrial proteomics by reducing mitochondrial content and abundance of electron transport chain complexes inducing mitochondrial dysfunction Thus, we assessed whether proteins of the oxidative complexes in the mitochondrial electron transport chain ETC and the mitochondria were affected by the lower UCP1 expression in siRNA- ADRB3 adipocytes.
Expression of the nuclear encoded genes and proteins of each complex of the ETC were similar in both siRNA- ADRB3 and control cells and independent of the absence or presence of UCP1 Supplemental Figure 3, A and B.
However, costaining with MitoTracker dye and an anti-UCP1 antibody revealed lower mitochondrial and UCP1 protein levels Figure 1H and Supplemental Figure 2, B and C in siRNA- ADRB3 adipocytes.
The mRNA levels of acetyl-CoA acetyltransferase ACAT1 and medium chain acyl-CoA dehydrogenase ACADM , genes coding for enzymes that oxidize fatty acids, were not significantly affected Figure 1K. Phosphocreatine cycling has been shown to contribute to oxidative metabolism in human brown adipocytes Loss of β 3 -AR impairs SCLV adipocyte cAMP accumulation and β-AR—mediated lipolysis.
Having demonstrated the effects of silencing ADRB3 on gene expression, we next assessed the functional implications. Since fatty acids are required for BAT thermogenesis 24 , 51 — 54 , we investigated the functional consequence of β 3 -AR deficiency on levels of the second messenger cAMP and lipolysis in ADRB3 -silenced adipocytes.
In the absence of ligand, suppression of ADRB3 alone lowers adenylyl cyclase activity, possibly due to the disruption of precoupled stable complexes formed between the β-AR and adenylyl cyclase, which consequently lowers basal cAMP.
A and B Basal, forskolin-stimulated Fsk 10 μM and isoproterenol-stimulated Iso 1 μM , cAMP concentration A and glycerol release B in siRNA-Ctrl and siRNA- ADRB3 adipocytes.
C RNA levels of lipolytic genes PNPLA2 , LIPE , and ABHD5 in siRNA-Ctrl and siRNA- ADRB3 adipocytes. D Protein expression of pHSL, pHSL, HSL, ATGL, CGI, perilipin, and actin in cell lysates following Fsk treatment.
E — G Quantification of HSL E , ATGL F , and CGI G from Western blotting analysis. H Glycerol released into the incubation media following dose-dependent treatment with mirabegron , nM in siRNA-Ctrl— and siRNA- ADRB3 —transfected adipocytes.
I Glycerol released by siRNA-Ctrl and siRNA- ADRB3 adipocytes treated with 10 μM of relatively selective human β 1 agonist dobutamine, β 2 agonist terbutaline, and β 3 agonist mirabegron. Fsk 10 μM and Iso 1 μM were used as positive controls of agonist-induced lipolysis.
Data are represented as mean ± SEM. Gene expression data are normalized to siRNA-Ctrl adipocytes and expressed on a log 10 scale. Next, we measured basal and Fsk-stimulated lipolysis and found no difference between the control and silenced ADRB3 cells in unstimulated lipolysis.
Therefore, we evaluated the gene expression of patatin like phospholipase domain containing 2 PNPLA2 ; lipase E, hormone sensitive type LIPE ; and abhydrolase domain containing 5, lysophosphatidic acid acyltransferase ABHD5 , that respectively encode adipocyte triglyceride lipase ATGL , hormone sensitive lipase HSL , and CGI, a direct activator of ATGL.
ATGL and HSL are the predominant lipases in BAT that catalyze the first 2 steps of triglyceride breakdown. There were no differences in the expression of these genes between the control and ADRB3 -siRNA—transfected groups Figure 2C. Immunoblotting showed similar levels of actin, perilipin, total HSL, and PKA-phosphorylated HSL pHSL and pHSL in siRNA- ADRB3 cells relative to siRNA-Ctrl adipocytes at baseline Figure 2, D and E and in response to Fsk Figure 2D.
In contrast, independent of Fsk treatment, ATGL protein levels were significantly lower in the siRNA- ADRB3 adipocytes Figure 2, D and F. However, the siRNA- ADRB3 adipocytes had higher CGI protein expression, which did not further increase upon Fsk treatment Figure 2, D and G.
This suggests a defect in the translation but not transcription of ATGL, CGI, and HSL enzymes. Lower levels of ATGL and higher levels of CGI in the siRNA- ADRB3 adipocytes could explain the reduced intracellular triglyceride lipolysis even after Fsk treatment, an activator of lipolysis acting downstream of the cell surface receptors.
β 1 -AR and β 2 -AR have been implicated in human WAT and BAT triglyceride hydrolysis 32 , 35 — 37 , while the involvement of the β 3 -AR remains controversial 55 — Glycerol released by the control and ADRB3 cells was monitored following dose-dependent treatment with mirabegron.
Compared with unstimulated lipolysis, in the siRNA-Ctrl adipocytes, mirabegron induced lipolysis at nM, 1 μM, and 10 μM with 1. In contrast, in adipocytes with silenced ADRB3 , mirabegron-induced lipolysis was increased only at 10 μM, and the increase was 1. These data suggest that only at supraphysiological concentrations, mirabegron could be mobilizing FFA by binding to a combination of the small number of remaining β 3 -ARs in addition to the β 1 -ARs and β 2 -ARs.
We compared the effects of mirabegron on lipolysis with those caused by the relatively specific human β 1 -AR-and β 2 -AR agonists, dobutamine and terbutaline, and used Fsk and Iso as positive controls 61 , Strikingly, these responses were blunted after treatment with siRNA- ADRB3 Figure 2I.
These data indicate that intact ADRB3 is required for normal signal transduction downstream to all 3 β-ARs and AC. Besides reduced β 3 -AR signaling, the observed impairments in the thermogenic and lipolytic machinery could theoretically be attributed to the presence of an adrenergic receptor antagonist in the culture medium.
Propranolol did not have any effect on unstimulated lipolysis, showing that there was no adrenergic activator in the culture system Supplemental Figure 4A.
Furthermore, the increased glycerol release in response to all β-AR agonists was blunted in the presence of propranolol Supplemental Figure 4A. Since siRNA-Ctrl and siRNA- ADRB3 adipocytes are deprived of all hormones present within the differentiation cocktail when transfected, these data reinforce that the presence of ADRB3 is regulating the lipolytic and thermogenic machinery as evident by the lower tonic levels of cAMP Figure 2A and thermogenic genes, including UCP1 Figure 1, F and H.
Humans treated with niacin, which inhibits WAT and BAT intracellular lipolysis, have severe thermoregulatory defects, indicating that lipolysis is necessary for BAT thermogenesis 63 , First, we monitored oxygen consumption rate OCR without the activation of lipolysis and found an overall lower OCR in the siRNA- ADRB3 —transfected adipocytes Figure 3A.
Baseline respiration and nonmitochondrial respiration were, respectively, 8. We detected a significant impairment in the siRNA- ADRB3 adipocytes to increase ATP-linked respiration by 5. A and B OCR A and quantification of respiratory profile by differentiated siRNA-Ctrl and siRNA- ADRB3 transfected adipocytes B.
Next, to unambiguously examine the requirement of ADRB3 in the lipolytic activity to activate UCP1 thermogenic activity, we used Fsk to stimulate lipolysis. UCP1, activated by fatty acids released from intracellular lipolysis, acutely increases the rate of proton leak produced by uncoupled respiration.
Nonmitochondrial respiration was 9. The lower spare respiratory capacity in the siRNA- ADRB3 adipocytes also indicates mitochondrial dysfunction. Additionally, the lower nonmitochondrial respiration in the ADRB3 -transfected adipocytes compared with their controls suggests that silencing of ADRB3 could also affect nonmitochondrial sources of oxidation that are biologically relevant to maintain cellular respiration.
However, when converted with the basal glucose OCR of each transfection treatment, the siRNA- ADRB3 adipocytes displayed a similar ability to increase proton leak, ATP production, and FCCP-induced maximal glucose substrate oxidation compared with the control transfected adipocytes Figure 4C.
Expression of the principal cell surface glucose transporters GLUT1 and GLUT4 for glucose uptake, respectively encoded by SLC2A1 and SLC2A4 , was not different in the siRNA- ADRB3 and siRNA-Ctrl adipocytes Supplemental Figure 5C.
OCR A , quantification of basal respiration in the presence and absence of 25 mM glucose B , and respiratory profile C in siRNA-Ctrl— and siRNA- ADRB3 —transfected adipocytes when exposed to high glucose.
D — F ECAR after sequential addition glucose 25 mM , oligomycin, and 2-deoxyglucose D and quantification of baseline ECAR E and glycolysis and glycolytic capacity and reserve F in siRNA-Ctrl and siRNA- ADRB3 adipocytes. Next, we monitored glucose-induced glycolysis, the metabolic pathway that converts glucose into pyruvate or lactate, to determine whether glucose is properly metabolized for mitochondrial ATP production.
Glycolysis, measured after the injection of glucose, was adjusted for the nonglycolytic acidification rate to represent the ECAR from glycolysis. Overall, this suggests that the siRNA- ADRB3 adipocytes switch to glycolysis when energy demand increases to augment glucose consumption for mitochondrial ATP production and respiration to achieve thermogenic activation.
A — G The mRNA expression profiles of β-ARs A , thermogenic related genes B , mtDNA-encoded genes C , glucose transporters D , fatty acid oxidation genes E , fatty acid synthesis genes F , and lipolytic genes PNPLA2 , LIPE , and ABHD5 G in siRNA-Ctrl and siRNA- ADRB1 adipocytes after 48 hours of transfection.
H and I Fsk-stimulated 10 μM and Iso-stimulated 1 μM cAMP H and glycerol release I in siRNA-Ctrl and siRNA- ADRB1 adipocytes. J RNA levels of nuclear encoded ETC genes in siRNA-Ctrl and siRNA- ADRB1 adipocytes. K — M OCR trace K and quantification of basal respiration L and respiratory profile M by differentiated siRNA-Ctrl— and siRNA- ADRB1 —transfected adipocytes.
In the siRNA- ADRB3 adipocytes, basal and Fsk- and Iso-stimulated cAMP secretion was diminished compared with their siRNA-Ctrl adipocytes.
Similar to the siRNA- ADRB3 adipocytes, no differences were detected in the expression of PNPLA2 , LIPE , and ABHD5 Figure 5G. To further dissect the contribution of β 1 -AR and β 3 -AR on lipolysis and determine the functional profile of loss of the β 3 -AR, we used L, 68 , 69 , one of the very few human β 3 -AR antagonists available.
Pretreatment with L, followed by treatment with β-AR agonists had no effects on basal lipolysis, but L, significantly reduced lipolysis when adding β 1 -, β 2 -, or β 3 -AR agonists Supplemental Figure 4A.
These data are therefore consistent with the reduction in lipolysis seen with the siRNA- ADRB3 adipocytes. Next, we established the effects of silencing ADRB1 adipocytes on OCR in siRNA- ADRB1 adipocytes and observed a significantly higher respiratory rate in the siRNA- ADRB1 adipocytes compared with control cells Figure 5K.
When adjusted to basal OCR, siRNA- ADRB1 and control transfected adipocytes displayed similar ability to perform uncoupled respiration, produce ATP, and increase FCCP-stimulated and maximal respiration Figure 5M.
The increase in cellular respiration and loss of ATP5G1 expression in the siRNA- ADRB1 could be allowing protons to leak into the matrix or increase electron slippage that could result in increased OCR in the absence of proton translocation.
Although primary adipocytes model the physiological behavior occurring in vivo, there is a limited supply. Therefore, we investigated whether silencing ADRB3 in immortalized human brown preadipocytes from a separate subject 70 would affect UCP1 expression, lipolysis, and the thermogenic machinery.
Research Article Cell biology Fat burner for athletic performance Open Thermognesis Address correspondence to: Aaron M. Cypess, Diabetes, Endocrinology, and Obesity Branch, NIDDK, NIH, 10 Center Drive, Bethesda, MarylandUSA. Phone: cypess nih.Fat burner for athletic performance tissue lipoysis regulates whole-body energy homeostasis. Mammals have two major adipose Fat burner for athletic performance white adipose tissue WAT anx brown adipose tissue BAT.
WAT Sports and Recreation Events excess energy while BAT dissipates energy as heat for non-shivering thermogenesis. Some adipocytes Assessing body weight Thermogehesis, like brown adipocytes, lipolyis uncoupling protein-1 UCP1a protein that mediates heat oipolysis Thermogenesis and lipolysis ahd mitochondrial respiration from ATP Fat burner for athletic performance.
This Increase energy levels of adipocytes is recently Thermogenesis and lipolysis The quantity of beige adipocytes Thermogenseis during cold adaptation or sympathetic activation, a process referred to as WAT browning.
Assessing body weight of stored Thermogehesis energy for Assessing body weight during starvation or increased Liver cleanse capsules demand e.
A gene critically implicated lipokysis intracellular lipolysis is CGI Thermogeneais Gene Identification In mammals, CGI is ubiquitously expressed Theromgenesis the highest expression in fat.
It interacts with LD coat proteins and activates ATGL Adipose Triglyceride Lipolyysis to promote intracellular Coenzyme Q side effects. It was believed that Thegmogenesis lipolysis in BAT Thermognesis essential for thermogenesis, but this Assessing body weight not been examined in lipolgsis.
We surprisingly found Fat burners for amplified fat metabolism mice lacking CGI Assessing body weight Ane, i. This proposal is to define the underlying adaptive mechanisms.
Our preliminary studies suggest a central hypothesis: Thermoggenesis deficiency in intracellular lipolysis may reprogram BAT to take up more circulating thermogenic substrates derived from WAT lipolysis and diet and by inducing WAT thermogenesis through activation of the sympathetic nervous system.
We will test this hypothesis by examining BAT thermogenesis, BAT uptake of circulating substrates, and WAT thermogenesis under different temperature, sympathetic, and nutritional states.
We will also explore the origin of beige adipocytes in BAT-KO mice. Additionally, we will examine whether WAT lipolysis is required for thermogenesis and WAT browning in BAT-KO mice by using a pharmacological inhibitor of intracellular lipolysis and by simultaneous deletion of CGI in both BAT and WAT FAT-KO mice.
In some experiments, we will compare adipose CGI and ATGL KO mice to gain insights into other lipolytic roles of CGI Furthermore, we will define how BAT lipolysis regulates energy balance, glucose disposal, insulin sensitivity, and tissue lipid metabolism.
Finally, we will search for novel insights into how lipolysis deficiency augments adipose sympathetic drive. Thermogenesis dissipates energy. Perturbation of energy balance is a hallmark of common metabolic disorders, which contribute substantially to disease morbidity and mortality.
Findings from our studies hold promise of revealing novel approaches for control of overnutrition-induced metabolic disease. Adipose tissue plays a critical role in energy storage and dissipation, dysregulation of which underlines the obesity epidemic and its associated rise of metabolic disorders.
BAT thermogenesis was thought to require efficient breakdown of cytosolic triglyceride-rich lipid droplets intracellular lipolysisbut we found that selective inactivation of CGI, an activator of intracellular lipolysis, in energy-dissipating adipocytes does not impair cold adaptation, and we therefore propose to define the underlying adaptive mechanisms and its metabolic consequence.
Toggle navigation. Home Search Services Blog Contact About. The Role of Adipocyte Lipolysis in Thermoregulation Yu, Liqing Georgia State University, Atlanta, GA, United States. Share this grant: : :. Abstract Funding Institution Related projects Comments. Recent in Grantomics:. Recently viewed grants:.
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: Thermogenesis and lipolysis| Human Verification | C : TTC staining and quantification of iWAT and BAT of Chchd10 -AKO mice and WT. D : Blue native PAGE BN-PAGE of OXPHOS complexes in iWAT and BAT of Chchd10 -WT and Chchd10 -AKO mice. CI, CII, CIV, and CV of OXPHOS were detected with the NDUFA9 antibody CI , SDHB antibody CII , COX IV antibody CIV , and ATP5A1 antibody CV. ATP level in iWAT was analyzed by Mann-Whitney U test; other data in were analyzed by two-tailed unpaired Student t test. Data were analyzed by one-way ANOVA with Bonferroni multiple comparisons test. To test whether CHCHD10 functions in a cell autonomous manner, we disrupted Chchd10 expression by two sets of siRNAs in immortalized brown preadipocytes and then induced them to differentiate into mature adipocytes. Ablation of Chchd10 had no effect on adipogenic differentiation Supplementary Fig. Chchd10 disruption resulted in enlarged lipid droplets in adipocytes Fig. Both mRNA and protein levels of UCP1 were significantly downregulated by Chchd10 deficiency Fig. We also assessed the mitochondrial membrane potential, which is critical for ATP generation by OXPHOS and serves as an indicator for cell health, by JC-1 staining. Depletion of Chchd10 diminished the overall mitochondrial membrane potential Fig. We then knocked down Chchd10 expression in fat pads by adenovirus injection. We found that 1 BAT-specific Chchd10 deficiency increased the size of lipid droplets and reduced UCP1 levels in BAT Supplementary Fig. CHCHD10 regulated the thermogenesis in adipocytes. A — E : Immortalized brown preadipocytes were transfected with control siRNA siNC or si Chchd10 and then subjected to the adipogenic differentiation process. C : Analysis of CHCHD10, UCP1, and VDAC1 protein expression by Western blot. Pgc1a level was analyzed by Kruskal-Wallis test; other data were analyzed by one-way ANOVA with Bonferroni multiple comparisons test. E : Mitochondrial membrane potential with JC-1 staining of immortalized brown adipocytes green, low mitochondrial membrane potential; red, high mitochondrial membrane potential. F — H : Immortalized brown preadipocytes were infected with Ad-LacZ or Ad- Chchd10 and then induced to adipogenic differentiation. G : Protein levels of UCP1 and CHCHD10 in immortalized brown adipocytes. I and J : Preadipocytes in iWAT from Ucp1 -WT and Ucp1 -KO were induced to adipogenesis by beige adipocyte differentiation protocol. I : OCRs of Ucp1 -WT and Ucp1 -KO primary adipocytes transfected with siNC or si Chchd J : OCRs of Ucp1 -WT and Ucp1 -KO primary adipocytes infected with Ad-LacZ or Ad- Chchd To complement the loss-of-function model of Chchd10 , we overexpressed Chchd10 in immortalized brown adipocytes. Chchd10 overexpression led to smaller lipid droplets compared with control Fig. We then ectopically expressed Chchd10 in BAT and iWAT by adenovirus harboring the Chchd10 coding sequence. Overexpression of Chchd10 in BAT dramatically inhibited lipid deposition and upregulated UCP1 expression Supplementary Fig. Overexpression of Chchd10 in iWAT activated beige adipocytes and retained beige adipocyte morphology, even after mice were transferred from cold conditions to room temperature Supplementary Fig. These results collectively suggest that CHCHD10 promotes the activation and maintenance of brown and beige adipocytes. We then measured the regulation of VO 2 by CHCHD10 in Ucp1 knockout Ucp1 -KO adipocytes to clarify whether function of CHCHD10 was UCP1 dependent. In WT adipocytes, knockdown of Chchd10 decreased the OCR, while in Ucp1 -KO adipocytes, CHCHD10 had no effect Fig. Additionally, UCP1 ablation totally abolished the promoted effect on VO 2 induced by Chchd10 overexpression Fig. These data together demonstrate that UCP1 mediates function of CHCHD10 in energy expenditure. Having observed that CHCHD10 affected the activation of thermogenic fat, we then sought to explore the underlying mechanisms. Since Chchd10 deficiency in adipocytes impaired thermogenesis in the fasting state but not the fed state, we speculated that lipolysis is involved in the regulatory effects of CHCHD10 on thermogenesis because lipolysis, generating FFAs for thermogenesis, is highly responsive to fasting 6. Meanwhile, it has been reported that mice defective in adipose lipolysis are not cold sensitive when food is present but cold intolerant upon fasting, which is similar to the phenotype of Chchd10 -AKO mice 9. To test our hypothesis, we assessed lipolytic capacity by measuring the serum levels of glycerol and FFAs after fasting, which are lipolysis products. We found that serum levels of glycerol and FFAs were significantly reduced in Chchd10 -AKO mice compared with control Fig. The levels of ATGL and HSL, which catalyze the first step and the rate-limiting step in the hydrolysis of TGs, respectively, as well as the active form p -HSL, were dramatically decreased in all three fat tissue types from Chchd10 -AKO mice compared with the same tissues from WT mice Fig. CHCHD10 regulated lipolysis to promote the activation of thermogenic fat. A and B : Male mice were starved for 16 h and exposed at 4°C for 8 h. D : The protein levels of lipases in adipose tissues were measured in Chchd10 -WT and Chchd10 -AKO mice. F : Immortalized brown preadipocytes were infected with Ad-LacZ or Ad- Chchd10 with or without Atglistatin and then induced to differentiation. G and H : Mice were injected with Ad-LacZ or Ad- Chchd10 in iWAT, followed by injection of inhibitor of ATGL Atglistatin. The expression of FLAG-CHCHD10, ATGL, and UCP1 protein were measured in iWAT. H-E staining was used to analyze the iWAT morphology of mice. I — K : Atgl was overexpressed in iWAT of Chchd10 -AKO mice. UCP1 level and H-E staining of iWAT are shown. L : Protein levels of CHCHD10, ATGL, p-HSL, and HSL in adipose tissues of fed and fasted mice. eWAT, epididymal white adipose tissue. To this end, we replenished FFAs in the adipocytes and found that FFA addition reversed the decreased OCR in Chchddeficient cells Fig. We next overexpressed Chchd10 in immortalized adipocytes by adenovirus infection and then inhibited lipolysis using the ATGL inhibitor Atglistatin We found that Chchd10 overexpression increased VO 2 , while Atglistatin reversed this effect Fig. We repeated similar experiments in iWAT and found that Chchd10 induced beige adipocyte formation, as indicated by increased Ucp1 mRNA levels, and multilocular lipid droplets morphology, was diminished by Atglistatin Fig. We also overexpressed ATGL in iWAT of Chchd10 -AKO mice and found that replenishment of ATGL increased UCP1 level and decreased the size of lipid droplets, improving thermogenic adipocyte activation in Chchd10 -AKO mice Fig. In addition, we found that the CHCHD10, ATGL, HSL, and p-HSL protein levels were significantly increased in WAT and BAT from fasting mice Fig. These results indicate that Chchd10 modulates thermogenic fat activation through regulating lipolysis. Next, we sought to clarify the mechanism underlying the regulation of lipolysis by CHCHD It has been established that lipolysis is an energy-consuming process. Considering that ATP was reduced in Chchd10 -deficient cells Fig. To test this possibility, we disrupted Chchd10 expression in immortalized brown adipocytes and then treated the cells with ATP, followed by detection of lipolysis. We used liposomes to deliver ATP into adipocytes and detected a significant increased ATP level in immortalized brown adipocytes treated with ATP-liposome Supplementary Fig. Interestingly, we found that glycerol release was inhibited by Chchd10 ablation, while this was totally reversed after replenishment of ATP Fig. The decreased ATGL protein levels in Chchd10 -deficient cells were totally restored upon ATP treatment Fig. We then treated cells with FCCP to inhibit mitochondrial ATP production Fig. ATP generation regulated by CHCHD10 modulated lipolysis in adipocytes by controlling ATGL protein synthesis. A and B : Immortalized brown adipocytes were transfected with control siRNA siNC or siChchd The protein level of ATGL was measured. After liposome-encapsulated ATP treatment for 24 h, the protein levels of ATGL and VDAC1 were measured. G : Immortalized brown adipocytes were pretreated with or without ATP, and then CHX was used to inhibit protein synthesis and the half-life of ATGL protein measured. H : Immortalized brown adipocytes were pretreated with or without CHX for 2 h and incubated with liposome-encapsulated ATP for 24 h. ATGL protein level was detected by Western blot. I : Immortalized brown adipocytes treated with siNC or si Chchd10 following liposome-encapsulated ATP treatment for 24 h. The cells were then incubated with AHA to label newly synthesized protein. Immunoblot analysis of ATGL nascent protein by ATGL antibody was performed. J : Immortalized brown adipocytes treated with Ad-LacZ or Ad-Chchd De novo ATGL protein synthesis by AHA labeling of immortalized brown adipocytes was detected by Western blot. Ctrl, control. We then explored how ATP regulates ATGL expression. We found that ATP upregulated the ATGL protein level without affecting its mRNA level, indicating a posttranscriptional regulatory mechanism Fig. Translation regulation and stability are pivotal to the protein abundance. Further experiments showed that ATP treatment had little effect on the half-life of ATGL Fig. To test this possibility, we pretreated immortalized brown adipocytes with cycloheximide CHX to inhibit protein translation before ATP treatment. We found that ATP augmented ATGL protein levels, while pretreatment with CHX blocked the ATP-induced upregulation of ATGL Fig. To verify this possibility, we used AHA to label newly synthesized protein and found that knockdown of Chchd10 dramatically inhibited newly synthesized ATGL protein, while replenishment of ATP reversed it Fig. Consistently, Chchd10 overexpression promoted nascent protein synthesis of ATGL Fig. These results together reveal that Chchd10 deficiency leads to decreased ATP levels, which in turn downregulated lipolysis by inhibiting Atgl translation. We then challenged Chchd10 -AKO mice and WT littermates with HFD. No difference in body weight was observed between the two groups Fig. Glucose tolerance and insulin sensitivity were not significantly different Supplementary Fig. However, serum TG levels were significantly higher in Chchd10 -AKO mice compared with WT mice under both control diet and HFD conditions; serum TC and glucose levels were not significantly different Fig. In addition, lipid droplets were larger in adipose tissues of Chchd10 -AKO mice compared with those of WT mice Fig. Livers from Chchd10 -AKO mice exhibited increased lipid deposition compared with WT livers Fig. Consistent with hepatic steatosis, AST levels were significantly increased in Chchd10 -AKO mice, reflecting metabolic damage Fig. These data indicate that Chchd10 -AKO mice are prone to develop dyslipidemia. Ablation of CHCHD10 facilitated dyslipidemia and NAFLD upon HFD. TC level under NCD was analyzed by Mann-Whitney U test; other data were analyzed by two-tailed unpaired Student t test or with Welch correction. C : H-E staining showing morphology of iWAT, epididymal WAT eWAT , BAT, and liver from WT and KO mice fed an HFD. F : Representative infrared image of mice after cold exposure for 8 h. Data were analyzed by two-tailed unpaired Student t test or with Welch correction. Pgc1a , Dio2 , and Cidea levels in BAT were analyzed by Mann-Whitney U test; other data were analyzed by two-tailed unpaired Student t test or with Welch correction. L : The protein levels of ATGL and UCP1 in adipose tissues were measured in mice. The core temperature of Chchd10 -AKO mice was obviously reduced in the fasting state Fig. Examination of surface temperature showed similar results Fig. OCR and heat expenditure were reduced in Chchd10 -AKO mice in the fasting state Supplementary Fig. In support of thermogenesis defects, VO 2 in iWAT from Chchd10 -AKO mice was dramatically repressed Fig. ATP levels in adipose tissues were significantly lower Fig. Serum glycerol and FFA levels were reduced, reflecting decreased lipolysis in Chchd10 -AKO mice Fig. Consistently, both mRNA and protein levels of UCP1 were downregulated in adipose tissues of Chchd10 -AKO mice; the protein level of ATGL was decreased in adipose tissues from Chchd10 -AKO mice Fig. We next investigated Chchd10 expression in adipose tissues under different physiological statuses. Thermogenesis in BAT declines with age 29 ; therefore, we also assessed Chchd10 and Ucp1 expression in an aging mouse model. We found that Chchd10 expression was dramatically decreased in adipose tissues of aged mice accompanied by reduced expression of ATGL and UCP1 Fig. We also collected human adipose tissues, including SAT and PAT. PAT was recognized as brown-like adipose tissues 30 , Expression of both Chchd10 and Ucp1 were higher in PAT than SAT Fig. In PAT and SAT, Chchd10 mRNA level was highly positively correlated with Ucp1 Fig. These data overall suggest that CHCHD10 expression is positively associated with UCP1 and ATGL expression. CHCHD10 was positively correlated with UCP1 expression in adipose tissues. A : The transcription levels of Chchd10 and Ucp1 in adipose tissues from young 2-month-old and old month-old male mice. B : Western blot analysis of CHCHD10, UCP1, and ATGL expression levels in iWAT and BAT from young and old male mice. Chchd10 level was analyzed by Mann-Whitney U test; Ucp1 level was analyzed by two-tailed unpaired Student t test. On the basis of the present findings, we propose a potential mechanism by which CHCHD10 regulates lipolysis and thermogenesis in adipocytes. CHCHD10 is obviously increased during activation of thermogenic adipocytes and contributes to the organization of mitochondrial cristae. When CHCHD10 is disrupted, cristae are disorganized, leading to impaired OXPHOS complex assembly, thereby repressing ATP production. A decreased ATP level results in downregulation of lipolysis by reducing the ATGL protein level, which in turn inhibits thermogenesis and energy expenditure. Consequently, Chchd10 -AKO mice are prone to develop dyslipidemia and NAFLD. The current study highlights lipolysis as the key mediator of the regulatory effects of CHCHD10 on thermogenesis in adipose tissues, which is based on the following evidence. First, Chchd10 -AKO mice showed impaired thermogenesis and energy expenditure in the fasting state but not in the fed state, indicating that the processes involved in thermogenesis during fasting might be regulated by CHCHD Consistent with this phenotype of Chchd10 -AKO mice, mice defective in adipose lipolysis were not cold sensitive when food was present but exhibited cold intolerance under fasting 9. Second, lipolysis not only activated UCP1 protein but also increased mRNA expression of Ucp1. Both mRNA and protein levels of UCP1 were decreased in Chchd10 -AKO mice. As a mitochondrial located protein, CHCHD10 might indirectly regulate Ucp1 transcription, while lipolysis could be the potential mediator. Finally, and most importantly, lipolysis was dramatically inhibited upon Chchd10 ablation. When CHCHD10 is disrupted, cristae are disorganized, leading to impaired OXPHOS complex assembly, which is the primary mediator for the other phenotypes of CHCHD10 deficiency, including decreased ATP generation, impaired lipolysis, and thermogenesis. Decreased lipolysis in part might be a compensatory event for defective OXPHOS complexes caused by loss of CHCHD Nevertheless, decreased ATP was the driving factor for defective lipolysis. Lipolysis is an energy-consuming process. Inhibitors of mitochondrial OXPHOS, like rotenone and oligomycin, have been shown to repress hormone-induced lipolysis in adipose tissues, accompanied by low ATP levels 32 , 33 , which linked ATP production with lipolysis regulation. Extracellular ATP could also induce lipolysis in adipocytes These results indicated that lipolysis needs respiration coupled with phosphorylation, requiring a continuous supply of energy. ATP was required for cAMP-dependent protein kinase to phosphorylate HSL and stimulate lipolysis 34 ; however, little evidence regarding the direct regulatory effects of ATP on lipolysis have been reported. Actually, mitochondria physically and functionally interact with lipid droplets 35 ; thus, it is reasonable to hypothesize that local mitochondrial-generated ATP might induce lipolysis in lipid droplets. Indeed, our observation showed that Chchd10 deficiency led to decreased ATP levels, which in turn downregulated lipolysis by inhibiting Atgl translation. Mechanistically, by inhibiting HMG-CoA reductase, statins prevent cholesterol synthesis in the liver, thereby lowering intracellular cholesterol levels and altering hepatic VLDL secretion. Combining statin treatment with β 3 -AR agonism in E3L. CETP mice significantly reduced non-HDL-cholesterol and increased HDL-cholesterol in the plasma and non-significantly reduced atherosclerotic lesion size relative to statin alone. Mechanistically, PCSK9 inhibitors block the PCSK9-induced intracellular transport of LDLR into lysosomes for degradation, thereby decreasing cholesterol via increased hepatic uptake of TRL remnants and LDL. CETP mice, BAT activation by β 3 -AR agonism on top of alirocumab treatment significantly reduced plasma non-HDL-cholesterol, increased HDL-cholesterol and tended to further attenuate atherosclerosis development compared to alirocumab alone. Bile acid sequestrants bind to bile acids in the small intestine and therefore inhibit intestinal reabsorption. This leads to a reduction of bile acids in the circulation, which is sensed by hepatocytes and in turn the expression of LDLR and cholesterol conversion into bile acids is upregulated, resulting in decreased plasma LDL-cholesterol and reduced CVD risk. This is possibly due to elevated intestinal reabsorption resulting in an increased bile acid flux to the liver, which consequently downregulates bile acid synthesis. Whilst activation of BAT and browning of WAT creates an anti-atherogenic lipoprotein profile in clinically relevant mouse models on top of classical lipid-lowering agents, studies addressing the role of thermogenic adipose tissue in human lipoprotein metabolism and cardiovascular health are still scarce. In a 5-year follow-up study including 31 healthy subjects, cold-induced BAT activity as determined by [ 18 F]FDG uptake and [ 15 O]H 2 O perfusion was shown to correlate with lower carotid intima-media thickness and higher carotid elasticity via vascular imaging. CETP mice revealed that BAT activation causally reduces plasma triglycerides and increases HDL-cholesterol, 5 a similar relationship is thus likely operative in humans and may explain the inverse relation between BAT activity and CVD risk. A cross-over clinical study demonstrated that short-term cold exposure of young men not only increased the plasma concentration of small HDL particles, but also enhanced ATP-binding cassette A1 ABCA1 -dependent cholesterol efflux from macrophages to HDL as measured in vitro , 30 which is suggestive of higher reverse cholesterol transport in subjects in the presence of BAT activity. Notably, the association between the presence of metabolically active BAT and lower risk of coronary artery disease, congestive heart failure, and hypertension was found stronger in individuals who are overweight or obese as compared to lean individuals, 11 possibly suggesting that populations at high risk for CVD may benefit more from BAT-targeted therapy. Reassuringly, although obese individuals showed blunted expression of thermogenic genes in BAT 78 and decreased glucose uptake by the tissue, 79 adipocyte progenitors isolated from BAT of obese individuals can differentiate into thermogenic adipocytes at an equal frequency as those isolated from lean individuals, and the resulting differentiated brown adipocytes displayed comparable basal and noradrenalin-stimulated mitochondrial respiration. Besides the observed beneficial relation between the presence of BAT and CVD in humans see Section 6 , cold exposure has been shown to beneficially affect several risk factors for CVD, including adiposity and insulin resistance. Adiposity results from excessive energy intake relative to energy expenditure, or alterations in nutrient partitioning. Acute cold exposure increased resting energy expenditure in both lean 81—83 and obese 84 participants, and notably such increases were only evident 82 or more pronounced 83 in BAT-positive individuals i. with detectible [ 18 F]FDG uptake by BAT depots. Even though BAT activity is generally assessed using the glucose tracer [ 18 F]FDG, the cold-induced increase in energy expenditure was mainly explained by an increase in lipid oxidation. L and TAK did not reduce body fat mass. Alternatively, it is well possible that BAT activity simply improves overall metabolic health, rather than reducing adipose tissue mass per se. In line with this notion, a very recent study has suggested that after correcting for BMI, the presence of active BAT, as measured by [ 18 F]FDG uptake, was associated with decreased visceral adipose tissue and increased subcutaneous adipose tissue, 91 a phenotype that is typically associated with better metabolic health. BAT has also been implicated in glycaemic control. In healthy lean humans, acute cold stimulation 18°C 92 or 1-month cold acclimation i. Thus, studies have unequivocally demonstrated that cold exposure activates BAT, enhances energy expenditure, and improves glycaemic control. The relative contribution of BAT and other metabolic organs needs to be better understood, but at the very least it seems that the presence of cold- activate d BAT is associated with metabolic health. In , Cypess et al. Indeed, transcriptomic analysis of human BAT biopsies showed that abundance of β 2 -AR far exceeds that of β 3 -AR, while β 3 -AR is the dominant AR in mouse BAT. The recent finding regarding the prominent role of β 2 -AR in human BAT activation, however, opened up new opportunities for BAT as a therapeutic target in cardio metabolism. Interestingly, the amino acid sequence of human β 2 -AR is highly polymorphic. These findings thus imply that β 2 -AR agonism may be the way forward in adrenergic BAT activation, and further studies are warranted to assess whether this can effectively and safely activate human BAT in vivo. Besides cold-mediated sympathetic stimulation and pharmacological β-AR agonism, stimulation of two hormonal pathways also potently activate BAT and are worth noting as they lower atherosclerosis in preclinical models and improve risk factors for CVD in humans see also the graphical summary in Figure 3. Firstly, treatment of mice with recombinant human FGF21 enhanced the uptake of glucose and triglyceride-derived FAs from TRLs by BAT and promoted WAT browning, , which normalized glycaemia and reduced plasma triglycerides. Graphical summary of promising therapeutic interventions to promote thermogenic adipose tissue activity and their effects on risk factors for CVD in humans. Similar to FGF21, studies of glucagon-like peptide 1 receptor GLP-1R agonism have also shown promising results. In lean mice, intracerebroventricular administration with the GLP-1R agonist liraglutide activated BAT thermogenesis as evident from decreased intracellular lipid content in combination with increased interscapular temperature In both lean and diet-induced obese mice, another GLP-1R agonist, exendin-4, was shown to increase UCP1 protein content in BAT. Indeed, patients with type 2 diabetes using liraglutide showed less death from cardiovascular causes and a lower frequency of nonfatal myocardial infarction and stroke. CETP mice have shown that GLP-1R agonists reduced atherosclerosis development via reducing inflammation in atherosclerotic plaques. Furthermore, glucose-dependent insulinotropic polypeptide receptor GIPR agonism was proposed to enhance the metabolic effects of GLP-1R agonism. Taken together, there is compelling evidence for a relationship between the presence of metabolically active BAT in humans and lower CVD risk. The still unresolved question, however, is to what extent the observed associations imply causality or merely reflect overall metabolic health. Cold interventions have been shown to activate BAT activity and thermogenesis, and large prospective intervention studies applying cold interventions will be needed to prove causality. In addition, genetic polymorphisms determining the thermogenic capacity of adipose tissue may be identified to allow proof of causality between adipose tissue thermogenesis and CVD risk in large Mendelian-randomization studies. Experimental studies in mice have convincingly shown that thermogenic activity in adipose tissue enhances lipolytic processing of TRLs, resulting in FA uptake by adipocytes and consequently promotes liver uptake of TRL remnants provided that an intact human-like ApoE-LDLR pathway is present Table 1. Together, these result in combined attenuation of hypertriglyceridaemia and hypercholesterolaemia and reduce atherosclerosis development. This anti-atherosclerotic effect is likely further enhanced by elevated reverse cholesterol transport, which is driven by enhanced cholesterol efflux capacity of HDL as a consequence of increasing lipid transfer from TRLs to HDL during lipolytic processing. In humans, BAT activity inversely correlates with circulating triglyceride and HDL-cholesterol levels and CVD prevalence and seems to protect against additional risk factors for CVD including adiposity and insulin resistance. Combined with the findings from preclinical studies that thermogenic adipose tissue activation adds to the lipid-lowering and antiatherogenic effects of classical lipid-lowering strategies i. Obviously, further research is needed to reveal whether promotion of BAT activity or browning of WAT can be used to treat dyslipidaemia and atherosclerotic CVD in humans, especially in those individuals who are at high risk for CVD. FGF21 and GLP-1R agonism likely in combination with GIPR agonism activate BAT and promote browning of WAT in mice and are promising therapeutic strategies to treat human atherosclerotic CVD. Further clinical studies are warranted to assess their efficacy to reduce atherosclerotic CVD, as well as the involvement of BAT activation therein. 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| Thermogenic Fat: Brown and Beige Adipocytes | We found that Chchd10 expression was dramatically decreased in adipose tissues of aged mice accompanied by reduced expression of ATGL and UCP1 Fig. enw EndNote. Gillilan, R. Reviewed by: Vibha Singhal , Massachusetts General Hospital, United States Marco Infante , University of Miami, United States. Upon hormone binding, the α-subunit of the receptor-coupled trimeric G s protein dissociates and stimulates adenylate cyclase, resulting in cAMP synthesis Else, P. |
| Lipolysis: cellular mechanisms for lipid mobilization from fat stores | Nature Metabolism | After Fat burner for athletic performance washes Thrmogenesis 0. Schaltenberg, N. InAssessing body weight Thermogenesks colleagues described hormone-sensitive lipase HSL as Assessing body weight Thermogeneesis hydrolase in Thermogfnesis degradation Chitosan for nanoparticles TGs and DGs and the role of monoglyceride lipase MGL in MG hydrolysis in adipocytes 4. Cell49—61 Image acquisition was performed with an upright Zeiss Axio Observer Z1 microscope using Zen software ; Zeiss. The results from the ATGL KO mouse models tell a compelling story that lipolysis in brown and beige adipocytes is dispensable for body temperature maintenance, but lipolysis in WAT is required. |
| Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice | Moreover, variations in housing temperature also impact the brown and beige adipocyte population and alter body weight in response to shifts in energy expenditure Fischer et al. Recently, our study revealed that, in an increased beige fat-enriched mouse model, fatty acid-binding protein aP2 -promoter Prdm16 transgenic mice aP2-PRDM16 transgenic × Ucp1 KO mice could maintain their temperature in a cold environment although mice totally lacking Ucp1 could not Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. These data support the role of SLN in regulating systemic energy expenditure via calcium uncoupling |
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