Thermogenesis In Brown Adipocytes Research Articles

Cell-autonomous Action of the FGF19 Promotes UCP1 Expression and Function in Human Brown Adipocytes

Fibroblast growth factor 19 (FGF19) is an intestine-derived hormone that regulates glucose and energy metabolism. Central and systemic administration of human FGF19 in mice promotes increased energy expenditure and body weight loss through mechanisms that are not fully understood. In this study, we investigated whether FGF19 can activate thermogenesis in brown adipocytes (BA) in a cell-autonomous manner. We differentiated immortalized human brown preadipocytes into mature adipocytes with adipogenic induction media in the presence and absence of FGF19 for 18 days to evaluate the effects of FGF19 on adipogenesis and thermogenesis. Through qPCR and RNA-sequencing analyses, we observed that FGF19 receptors were expressed in both brown preadipocytes and mature BA. However, the obligatory FGF19 co-receptor, β-klotho, was not expressed in preadipocytes, suggesting that the effects of FGF19 must occur preferentially in mature BA. Lipid staining with Oil Red O as well as gene expression of the adipogenic markers fatty acid binding protein (FABP4) and peroxisome proliferator activated receptor-γ (PPAR-γ) showed that adipogenesis was not affected by FGF19. We then treated mature BA with FGF19 (100 ng/mL) acutely and chronically to evaluate FGF19-induced changes in signaling, gene transcription, and thermogenic function. FGF19 signaling was assessed by measuring ERK1/2 phosphorylation levels, which increased within 5 min and remained elevated for at least 30 min after treatment. Using Seahorse assays, we observed that 24-hour FGF19 treatment promoted increased basal respiration, ATP production, and proton leak in human BA, indictive of enhanced mitochondrial function. Since proton leak across the inner membrane through the uncoupling protein 1 (UCP1) generates heat, we assessed the expression of UCP1 and other thermogenic genes. Interestingly, FGF19 treatment specifically increased UCP1 gene expression without affecting other classical adrenergic-mediated thermogenic genes, such as deiodinase 2 (DIO2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), PR domain containing 16 (PRDM16), and cell death-inducing DNA fragmentation factor A (CIDEA). These findings suggest that FGF19 regulates UCP1 expression through non-canonical pathways. Future work will elucidate the mechanism by which FGF19 promotes UCP1 gene expression in mature BA. Taken together, FGF19 stimulates ERK1/2 phosphorylation and UCP1 expression in human BA, leading to enhanced mitochondrial respiration. These results provide new mechanistic insights into FGF19’s effects on metabolic regulation. Topic subcategories: Adipocyte biology. Funding sources: Sao Paulo Research Foundation (FAPESP): 2022/15148-2 and NIH R01 DK102898. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mitochondrial flashes are interlinked with adaptive thermogenesis in brown adipocytes

Mitochondrial flash (mitoflash) is the electrochemical excitation of a single mitochondrion and plays diverse signaling roles in a variety of cells. From the viewpoint of bioenergetics, it represents the transient uncoupling of mitochondrial respiration from ATP synthesis. Brown adipose tissue (BAT) produces heat, primarily via mitochondrial uncoupled respiration. Here, we aim to illustrate the mitoflash activity in BAT thermogenesis. We show that BAT mitochondria undergo stochastic and intermittent mitoflashes at the levels of isolated mitochondria, cultured brown adipocytes, and even intact BAT. A BAT mitoflash contains multiple signals, including transient depolarization of mitochondrial membrane potential, transient matrix alkalization, and bursting production of reactive oxygen species. Importantly, thermogenic activation by β3-adrenergic stimulation dramatically augments mitoflash incidence, with mild effects on its unitary characteristics. Ablation of the thermogenic uncoupling protein 1 (UCP1) showed little effect on mitoflash biogenesis during heat production. Collectively, our results suggest that mitoflash might constitute an elemental signaling activity of mitochondria to regulate BAT thermogenesis.

Therapeutic potential of AAV-FL-Klotho in obesity: Impact on weight loss and lipid metabolism in mice

Klotho, an anti-aging protein, has gained attention for its protective effects against various diseases, including metabolic disorders, through recombinant Klotho administration. However, the potential of Klotho as a target for gene therapy requires further exploration, as it remains relatively understudied in the context of metabolic disorders. In this study, we demonstrate that AAV-full length(FL)-Klotho administration induces weight loss in mice and provides protection against high-fat diet (HFD)-induced obesity and hepatic steatosis, concurrently reducing the weights of white adipose tissue and liver. AAV-FL-Klotho administration also enhanced thermogenic gene expression in brown adipose tissue (BAT) and improved the morphology of interscapular BAT. The weight loss effect of AAV-FL-Klotho was found to be, at least in part, mediated by UCP1-dependent thermogenesis in brown adipocytes, potentially influenced by hepatokines secreted from AAV-FL-Klotho-transduced hepatocytes. These findings suggest that AAV-FL-Klotho is an attractive candidate for gene therapy to combat obesity. Nevertheless, unbiased experiments have also revealed disturbances in lipid metabolism due to AAV-FL-Klotho, as evidenced by the emergence of lipomas and increased expression of hepatic lipogenic proteins.

The dairy-derived peptide Miltin exerts anti-obesity effects by increasing adipocyte thermogenesis.

Growing research has highlighted that the consumption of dairy products improves the metabolic health in obese individuals by functioning as regulatory modulators. However, the molecular basis of this effect remains largely unknown. Herein, we report a dairy-derived peptide, which we named Miltin, that activates the thermogenesis of brown adipocytes and increases white adipocyte browning. Previously, Miltin was merely identified for its antioxidant capacity, although it is commonly present in different dairy products. In this study, we revealed the effect of Miltin in modulating adipose thermogenesis and further explored its potential in treating obesity through in vivo and in vitro strategies. The administration of Miltin in mice fed with a high-fat diet resulted in enhanced thermogenesis, improved glucose homeostasis, and reduced body mass and lipid accumulation, indicating the anti-obesity effect of Miltin. Genomic analysis revealed that Miltin modulates thermogenesis by inducing the activation of the MAPK signaling pathway by preferentially interacting with GADD45γ to promote its stability. Together, our findings indicate that Miltin's role in initiating the thermogenesis of adipocytes makes it a potential anti-obesity therapy for future development.

SAT430 Effect Of Organochlorine Pesticides On Brown Adipose Thermogenesis

Abstract Disclosure: S. Huang: None. J.A. Jugan: None. J. Harrigan: None. A. Singla: None. V. Huang: None. C.M. Mann: None. M. La Merrill: None. Mammalian non-shivering thermogenesis is canonically controlled by β-adrenergic signaling in brown adipose tissue. The β-adrenergic receptors Adrb1, Adrb2, and Adrb3 receive the signals from upstream sympathetic neurons, activate adenylyl cyclase, and increase the expression of uncoupled protein-1 (UCP1) which dissipates energy to produce heat. The banned but persistent pesticide dichlorodiphenyltrichloroethane (DDT) along with its metabolite, dichlorodiphenyldichloroethylene (DDE), jointly referred to as DDX, are consistently associated with increased risk of present-day obesity and type II diabetes. In addition, DDX reduced body temperature by reducing sympathetic axons innervation in mice. However, the effect of DDX on the expression of β-adrenergic receptors and thermogenesis in brown adipocytes and other mammals is unclear. Therefore, the association between DDX exposure and the expression of β-adrenergic receptors and thermogenesis in vitro and in vivo was investigated. To this aim, Sprague-Dawley (SD) rats were fed high-fat diet and gavage of either a very low dose DDX mixture (5.6μg/kg weekly for 4 weeks) or olive oil vehicle control. DDX caused a significant reduction in body temperature after two weeks without significant changes in caloric intake or food efficiency. Notably, among all the β-adrenergic receptors, only Adrb3, and Ucp1 were downregulated in the brown adipose of DDX-treated rats. These results suggest that DDX reduces body temperature by attenuating Adrb3 expression in rat brown adipose tissue. To test whether this could explain the previously observed risk of human obesity associated with DDX exposure, we used immortalized human brown adipocytes to evaluate the effect of DDX on the RNA expression of β-adrenergic receptors, UCP1, and thermogenic function. As observed in rat brown adipose, DDT and DDE each reduced the expression of ADRB3 and UCP1, but not ADRB1 or ADRB2 in immortalized human brown adipocytes. Further, DDT and DDE each decreased heat produced by the human brown adipocytes. In addition, the reduced expression of UCP1 in DDX-treated human brown adipocytes was dependent on the presence of adenylyl cyclase (AC) activator, forskolin, demonstrating that the expression of UCP1 can be rescued by bypassing the upstream β3-adrenergic receptor. In conclusion, this evidence supports the hypothesis that obesogenic pesticides, DDT and DDE, attenuate thermogenesis by impairing brown adipocyte expression of the β3-adrenergic receptor and UCP1 in several mammalian species. Presentation: Saturday, June 17, 2023

Phosphorylated YBX2 is stabilized to promote glycolysis in brown adipocytes

Y-box binding protein 2 (YBX2) is an essential modulator of brown adipose tissue activation, yet the regulation on its own expression and the involved mechanism remains largely unknown. Herein, we report the YBX2 protein level, but not mRNA level, is induced in response to acute β-adrenergic signaling. In this context, YBX2 is a dual substrate for both AMPK and Akt2. The phosphorylation at Thr115 by AMPK or at Ser137 by Akt2 facilitates YBX2 accumulation in brown adipocytes by decreasing ubiquitination-mediated degradation. Beyond stabilizing PGC1α mRNA, increased YBX2 upon thermogenic activation assists the expression of glycolytic enzymes, promotes glucose utilization and lactate production. Mechanistically, YBX2 modulates translation of glycolytic genes via direct binding to 5'-UTRs of these genes. Together these findings suggest YBX2 is responsive to thermogenic stimuli by phosphorylation modification, and stabilized YBX2 helps to boost glycolysis and thermogenesis in brown adipocytes.

IFI27 Integrates Succinate and Fatty Acid Oxidation to Promote Adipocyte Thermogenic Adaption.

Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in β-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.

Transcriptomic Analysis Reveals Fibroblast Growth Factor 11 (FGF11) Role in Brown Adipocytes in Thermogenic Regulation of Goats.

Brown adipose tissue (BAT) is the main site of adaptive thermogenesis, generates heat to maintain body temperature upon cold exposure, and protects against obesity by promoting energy expenditure. RNA-seq analysis revealed that FGF11 is enriched in BAT. However, the functions and regulatory mechanisms of FGF11 in BAT thermogenesis are still limited. In this study, we found that FGF11 was significantly enriched in goat BAT compared with white adipose tissue (WAT). Gain- and loss-of-function experiments revealed that FGF11 promoted differentiation and thermogenesis in brown adipocytes. However, FGF11 had no effect on white adipocyte differentiation. Furthermore, FGF11 promoted the expression of the UCP1 protein and an EBF2 element was responsible for UCP1 promoter activity. Additionally, FGF11 induced UCP1 gene expression through promoting EBF2 binding to the UCP1 promoter. These results revealed that FGF11 promotes differentiation and thermogenesis in brown adipocytes but not in white adipocytes of goats. These findings provide evidence for FGF11 and transcription factor regulatory functions in controlling brown adipose thermogenesis of goats.

START domain-mediated nuclear translocation of Them1 regulates the expression of metabolic genes relative to thermogenesis in brown adipocytes

Thioesterase superfamily member 1 (Them1) is a long-chain fatty acyl-CoA thioesterase that is highly expressed in brown adipose tissue (BAT), where it limits energy expenditure. Them1 is comprised of tandem enzymatic domains and a C-terminal lipid-binding steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. Fatty acid binding to the START domain stabilizes the enzymatic domains and increases activity, whereas lysophosphatidylcholine (LPC) acts in the opposite manner. In brown adipocytes, Them1 localizes to puncta within the cytoplasm, but diffuses in response to β-adrenergic stimulation after which it is also found in the nucleus. The aim of this study was to determine the mechanism of Them1 nuclear trafficking and the metabolic consequences. METHODS: Identification of a putative nuclear localization signal (NLS) was determined by computational analysis. Full-length, NLS-deleted, or truncated Them1 cDNA constructs were cloned and linked to EGFP. Plasmid or adenoviral vectors were transfected into immortalized brown adipose cells (iBAs) that do not express Them1. Them1 was visualized by live cell confocal imaging via EGFP and with NucSpot nuclear staining. Signal quantification was performed with Imaris software. Them1 nuclear localization was evaluated in the presence or absence of norepinephrine (NE), leptomycin B, cycloheximide, or lipids that bind the START domain. Them1 nuclear localization was also quantified in BAT from mice treated with a β3-adrenergic receptor agonist, CL316,243. mRNA expression in iBAs expressing full-length or NLS-mutant Them1 in response to NE was determined by RNA-Seq. RESULTS: In the diffuse state, Them1 localized to the nucleus in a time-dependent manner. The NLS resides in a hinge region between the thioesterase domains and the START domain. Deletion of either the NLS or the START domain blocked nuclear targeting. Conversely, truncated Them1 containing only the START domain was targeted to the nucleus. Entry into the nucleus was balanced by trafficking out of the nucleus and new protein synthesis was not required, as evidenced by using leptomycin B to block nuclear efflux and cycloheximide to block protein synthesis, respectively. Incubation of NE-stimulated iBAs with LPC promoted nuclear Them1 translocation. Them1 protein was also detected in the nucleus of BAT from wild-type mice in response to CL administration. Nuclear Them1 localization in iBAs was associated with down-regulated mRNA expression of genes that control lipid and glucose metabolism during cold adaptation. CONCLUSIONS: Our data suggest that LPC generated during thermogenesis binds and destabilizes the START domain, leading to exposure of the NLS and nuclear trafficking of Them1 in response to β-adrenergic stimulation. Once inside the nucleus, Them1 regulates the transcription of lipid and glucose metabolic enzymes that are required for chronic cold adaptation. This work was supported by NIH DK103046 to DEC, SJH, and EAO This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Optogenetic activation of UCP1-dependent thermogenesis in brown adipocytes

Brown adipocytes are unique in that they expend energy and produce heat to maintain euthermia through expression of uncoupling protein-1 (UCP1). Given their propensity to stimulate weight loss and promote resistance to obesity, they are a compelling interventional target for obesity-related disorders. Here, we tested whether an optogenetic approach could be used to activate UCP1-dependent thermogenesis in brown adipocytes. We generated brown adipocytes expressing a bacterial-derived photoactivatable adenylyl cyclase (bPAC) that, upon blue light stimulation, increases UCP1 expression, fuel uptake and thermogenesis. This unique system allows for precise, chemical free, temporal control of UCP1-dependent thermogenesis, which can aid in our understanding of brown adipocyte biology and development of therapies that target obesity-related disorders.

The ABA/LANCL1/2 Hormone/Receptor System Controls Adipocyte Browning and Energy Expenditure

The abscisic acid (ABA)/LANC-like protein 1/2 (LANCL1/2) hormone/receptor system regulates glucose uptake and oxidation, mitochondrial respiration, and proton gradient dissipation in myocytes. Oral ABA increases glucose uptake and the transcription of adipocyte browning-related genes in rodent brown adipose tissue (BAT). The aim of this study was to investigate the role of the ABA/LANCL system in human white and brown adipocyte thermogenesis. Immortalized human white and brown preadipocytes, virally infected to overexpress or silence LANCL1/2, were differentiated in vitro with or without ABA, and transcriptional and metabolic targets critical for thermogenesis were explored. The overexpression of LANCL1/2 increases, and their combined silencing conversely reduces mitochondrial number, basal, and maximal respiration rates; proton gradient dissipation; and the transcription of uncoupling genes and of receptors for thyroid and adrenergic hormones, both in brown and in white adipocytes. The transcriptional enhancement of receptors for browning hormones also occurs in BAT from ABA-treated mice, lacking LANCL2 but overexpressing LANCL1. The signaling pathway downstream of the ABA/LANCL system includes AMPK, PGC-1α, Sirt1, and the transcription factor ERRα. The ABA/LANCL system controls human brown and "beige" adipocyte thermogenesis, acting upstream of a key signaling pathway regulating energy metabolism, mitochondrial function, and thermogenesis.

Full activation of thermogenesis in brown adipocytes requires Basigin action.

Exploring mechanisms responsible for brown adipose tissue's (BAT) high metabolic activity is crucial to exploit its energy-dissipating ability for therapeutic purposes. Basigin (Bsg), a multifunctional highly glycosylated transmembrane protein, was recently proposed as one of the 98 critical markers allowing to distinguish 'white' and 'brown' adipocytes, yet its function in thermogenic brown adipocytes is unknown. Here, we report that Bsg is negatively associated with obesity in mice. By contrast, Bsg expression increased in the mature adipocyte fraction of BAT upon cold acclimation. Additionally, Bsg levels were highly induced during brown adipocyte maturation in vitro and were further increased upon β-adrenergic stimulation in a HIF-1α-dependent manner. siRNA-mediated Bsg gene silencing in cultured brown adipocytes did not impact adipogenesis nor mitochondrial function. However, a significant decrease in mitochondrial respiration, lipolysis and Ucp1 transcription was observed in adipocytes lacking Bsg, when activated by norepinephrine. Furthermore, using gas chromatography/mass spectrometry-time-of-flight analysis to assess the composition of cellular metabolites, we demonstrate that brown adipocytes lacking Bsg have lower levels of intracellular lactate and acetoacetate. Bsg was additionally required to regulate intracellular AcAc and tricarboxylic acid cycle intermediate levels in NE-stimulated adipocytes. Our study highlights the critical role of Bsg in active brown adipocytes, possibly by controlling cellular metabolism.

5-Heptadecylresorcinol Regulates the Metabolism of Thermogenic Fat and Improves the Thermogenic Capacity of Aging Mice via a Sirtuin 3–Adenosine Monophosphate-Activated Protein Kinase Pathway

5-Heptadecylresorcinol (AR-C17), a well-known biomarker for whole grain rye consumption, is a primary homolog of alkylresorcinols. In this study, the effects of AR-C17 on the thermogenesis of brown adipocytes and 3T3-L1 adipocytes were investigated. The results showed that AR-C17 increased sirtuin 3 (Sirt3) expression, and the expressions of specific thermogenic genes in adipocytes were increased. Furthermore, AR-C17 increased the mitochondrial functions during the thermogenic activation of adipocytes. In in vivo study, AR-C17 increased the cold tolerance and thermogenic capacity of adipose tissues in aging mice. In addition, Sirt3 activity was required for AR-C17-induced thermogenesis. Meanwhile, AR-C17 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and AMPK was involved in the regulation of AR-C17 on thermogenic adipocytes. Mechanically, AR-C17 upregulated a Sirt3-AMPK positive-feedback loop in adipocytes and further increased the expression of uncoupling protein 1 to activate thermogenesis. This study indicated that AR-C17 could be a promising thermogenic activator of adipocytes to alleviate obesity and aging-associated metabolic diseases.

LPS-Induced Inhibition of miR-143 Expression in Brown Adipocytes Promotes Thermogenesis and Fever.

Fever is an important part of inflammatory response to infection. Although brown adipose tissue (BAT) thermogenesis is known to be potently influenced by systemic inflammation, the role of BAT during infection-induced fever remains largely unknown. Here, we injected mice with a low dose of LPS and found that low-dose LPS can directly induce thermogenesis of brown adipocytes. It is known that miR-143 is highly expressed in the BAT, and miR-143 knockout mice exhibited stronger thermogenesis under cold exposure. Interestingly, miR-143 was negatively correlated with an LPS-induced increase of TNFα and IL-6 mRNA levels, and the IL-6 pathway may mediate the inhibition of miR-143 expression. Moreover, miR-143 is down-regulated by LPS, and overexpression of miR-143 in brown adipocytes by lentivirus could rescue the enhancement of UCP1 protein expression caused by LPS, hinting miR-143 may be an important regulator of the thermogenesis in brown adipocytes. More importantly, the knockout of miR-143 further enhanced the LPS-induced increase of body temperature and BAT thermogenesis, and this result was further confirmed by in vitro experiments by using primary brown adipocytes. Mechanistically, adenylate cyclase 9 (AC9) is a new target gene of miR-143 and LPS increases BAT thermogenesis by a way of inhibiting miR-143 expression, a negative regulator for AC9. Our study considerably improves our collective understanding of the important function of miR-143 in inflammatory BAT thermogenesis.

A purinergic call to arms from dying brown adipocytes.

Brown adipocytes react to temperature and nutritional challenges by ramping up their metabolism and generating heat. This adaptation to changes in the environment is crucial for defending organismal homeostasis, but is impaired in obesity and during aging. Writing in Nature, Niemann et al. show that brown adipocytes become apoptotic under thermoneutral conditions and release ATP, which in turn is converted extracellularly into inosine. They further present evidence that pharmacological and genetic manipulations that enhance signalling of this purine metabolite stimulates thermogenesis in brown adipocytes and promotes metabolic health.

311-OR: Regulation of Brown Adipocyte Differentiation and Thermogenesis by Prostaglandin F2a

Brown adipocytes hold the potential to mitigate body fat accumulation and type 2 diabetes (T2D) via their specialized function in dissipating energy as heat, a process known as thermogenesis. To fuel their function, brown adipocytes release the bond energy of fat through lipolysis and β-oxidation; then, uncoupling cellular respiration releases this energy as physical heat. In addition to their energy-dissipating function, brown adipocytes can release factors, such as lipids, metabolites, peptides, or microRNA, to regulate metabolism. Signaling lipids have demonstrated roles in regulating thermogenesis in brown adipocytes by regulating lipid uptake and utilization. To further explore these pathways, we performed signaling lipidomics analysis in in vitro differentiated human brown adipocytes and found 15-keto-PGF2α was increased when treated with forskolin, an adenylyl cyclase activator that mimics adrenergic stimulation. Previous studies have shown PGF2α, the parent molecule of 15-keto-PGF2α, inhibits maturation, or adipogenesis, in white adipocyte cell lines by preventing the expression of key adipogenesis genes, such as PPARγ and C/EBPα. Similarly, PGF2α inhibits thermogenic gene expression in brown adipocyte cells. To explore and compare the functional activities of PGF2α and 15-keto-PGF2α, we characterized the dose-response relationship of these lipids on thermogenic gene and protein expression. We found that 15-keto-PGF2α is not as potent as PGF2α at inhibiting both thermogenic gene and protein expression. This suggests the conversion of PGF2α to 15-keto-PGF2α represents a significant signaling event to promote thermogenesis in brown adipocytes. Interestingly, carbonyl reductase 1, an enzyme that catalyzes this conversion, is regulated by treatment with the adrenergic agonist, norepinephrine, in vitro and by cold exposure in vivo. Targeting this conversion may be an attractive approach towards activating thermogenesis to mitigate obesity and T2D. Disclosure E.Fadumiye: None. S.Kodani: None. M.Kiebish: None. V.Bussberg: None. Y.Tseng: Consultant; Cellarity. Funding National Institutes of Health (R01DK122808)

312-OR: Glucose Oxidation in Brown Fat

In the United States, more than 70% of adults are overweight or obese, caused primarily by excess energy intake in modern society. Brown adipose tissue (BAT) can function as an “energy sink” in mammals, since BAT is specialized with uncoupling respiration, which burns energy to maintain body temperature. Unfortunately, thermogenesis in brown adipocytes dramatically declines in obese individuals, contributing to the development of obesity-related metabolic disorders. Although both lipids and glucose have been viewed as major energy substrates for thermogenesis, most of the early studies have been focusing on fatty acid oxidation. Recently, we found that BAT had the most active glucose oxidation among metabolic active tissues, and chronic cold exposure significantly enhanced glucose oxidation in mice BAT. Furthermore, in vivo administration of a mitochondrial pyruvate carrier (MPC) inhibitor impaired glucose oxidation and thermogenesis in BAT, which was consistent with the impaired thermogenesis of a recently published mouse model of constitutive BAT-selective deletion of MPC1 (Ucp1-MPC1-KO) . In order to directly study the role of MPC in mature brown adipocytes, we generated a Tet-on inducible Ucp1‑specific MPC2 knockout (Ucp1‑MPC2‑iKO) mouse model. As expected, Ucp1-MPC2-iKO mice couldn’t maintain body temperature upon acute cold exposure, after prolonged loss of MPC in mature brown adipocytes. Interesting, adult Ucp1-MPC2-iKO mice were cold-resistant, after the acute loss of MPC in the mature brown adipocytes, which were different from the constitutive Ucp1-MPC1-KO mice. Together, our study suggests that although glucose oxidation is essential to optimal BAT thermogenesis, MPC-independent metabolism exists to maintain glucose oxidation and thermogenesis in BAT. Disclosure L. Jiang: None. Q. Wang: None.

KCTD10 regulates brown adipose tissue thermogenesis and metabolic function via Notch signaling.

Brown adipose tissue (BAT) is emerging as a target to beat obesity through the dissipation of chemical energy to heat. However, the molecular mechanisms of brown adipocyte thermogenesis remain to be further elucidated. Here, we show that KCTD10, a member of the polymerase delta-interacting protein 1 family, was reduced in BAT by cold stress and a β3 adrenoceptor agonist. Moreover, KCTD10 level increased in the BAT of obese mice, and KCTD10 overexpression attenuates uncoupling protein 1 expression in primary brown adipocytes. BAT-specific KCTD10 knockdown mice had increased thermogenesis and cold tolerance protecting from high-fat diet (HFD)-induced obesity. Conversely, overexpression of KCTD10 in BAT caused reduced thermogenesis, cold intolerance, and obesity. Mechanistically, inhibiting Notch signaling restored the KCTD10 overexpression-suppressed thermogenesis. Our study presents that KCTD10 serves as an upstream regulator of Notch signaling pathway to regulate BAT thermogenesis and whole-body metabolic function.

A closer look at adipose tissue lymphatics and their markers.

Lymphatic vessels are found in most tissues, with the exception of the cornea and the central nervous system. Tissues that have high exposure to antigens, such as the skin and the intestine, have especially extensive lymphatic vascular networks. Despite being densely vascularized with blood vessels, adipose tissue is poorly permeated with lymphatic vasculature. Here, we focus on the recent advances in the research on adipose tissue lymphatics and present a lymphatic-focused analysis of published single-cell and single-nucleus RNA sequencing datasets of adipose tissues. Although lymphatic expansion in obesity may limit inflammation and promote glycerol efflux from adipose tissue, lymphatic endothelial cells (LECs) secrete factors that reduce brown adipocyte thermogenesis. Transcriptomic analyses of these cells show that they express common lymphatic markers such as Proxl, but datasets from different studies show great variation in gene expression values due to the low number of captured LECs, depot differences, and species-specific gene expression patterns. As the importance of LECs in the homeostasis of adipose tissue has become evident, investigators want to shed light on the specific interactions of lymphatics with other cell types in adipose tissues. Extracting LECs from readily available transcriptomics datasets provides a standpoint for investigators for future research. However, systematic studies are needed to reveal unique identities according to depot and species-specific LEC signatures.

Adipocyte Utx Deficiency Promotes High-Fat Diet-Induced Metabolic Dysfunction in Mice.

While the main function of white adipose tissue (WAT) is to store surplus of energy as triacylglycerol, that of brown adipose tissue (BAT) is to burn energy as heat. Epigenetic mechanisms participate prominently in both WAT and BAT energy metabolism. We previously reported that the histone demethylase ubiquitously transcribed tetratricopeptide (Utx) is a positive regulator of brown adipocyte thermogenesis. Here, we aimed to investigate whether Utx also regulates WAT metabolism in vivo. We generated a mouse model with Utx deficiency in adipocytes (AUTXKO). AUTXKO animals fed a chow diet had higher body weight, more fat mass and impaired glucose tolerance. AUTXKO mice also exhibited cold intolerance with an impaired brown fat thermogenic program. When challenged with high-fat diet (HFD), AUTXKO mice displayed adipose dysfunction featured by suppressed lipogenic pathways, exacerbated inflammation and fibrosis with less fat storage in adipose tissues and more lipid storage in the liver; as a result, AUTXKO mice showed a disturbance in whole body glucose homeostasis and hepatic steatosis. Our data demonstrate that Utx deficiency in adipocytes limits adipose tissue expansion under HFD challenge and induces metabolic dysfunction via adipose tissue remodeling. We conclude that adipocyte Utx is a key regulator of systemic metabolic homeostasis.