Promote Energy Expenditure Research Articles

1663-P: Estrogenic Regulation of Energy Balance in the Medial Amygdala

Compelling evidence has demonstrated that estradiol (E2) and estrogen receptors α/β (ERα/β) play critical roles in the central regulation of energy balance and glucose homeostasis. Our previous research proved that ERα in the medial amygdala (ERαMeA) mediates estrogenic actions to stimulate physical activity, promote energy expenditure, and prevent diet-induced obesity (DIO). Interestingly, ERβ is also highly expressed in the MeA neurons. To explore the metabolic functions of ERβMeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKOMeA) during adulthood by using AAV virus-mediated Cre-Lox site-specific recombination. When fed on a high-fat diet (HFD) but not a standard chow diet, both male and female ERβKOMeA mice showed decreased body weight gain and fat deposition, associated with a decrease in ambulatory activity. Consistently, we also observed an increase in energy expenditure of female ERβKOMeA mice during diet switching from chow to HFD, suggesting a diet-dependent regulatory role of ERβMeA in body weight control. In addition, both electrophysiology and immunohistochemistry staining results indicated that half of the ERαMeA neurons co-express ERβ. In these ERα&β co-expressing MeA neurons, ERα agonist propyl pyrazole trio (PPT) induced ERα-dependent depolarization, while ERβ agonist diarypropionitrile (DPN) induced ERβ-dependent hyperpolarization. Further, we found that the chemogenetic activation of ERαMeA neurons promotes physical activity and stimulates body thermogenesis, while the inhibition of ERβMeA neurons downregulates physical activity and body thermogenesis. In line with this, inhibition of ERβMeA neurons impaired cold-induced brown adipose tissue thermogenesis, resulting in lower rectal temperature during acute cold exposure. Collectively, our results support a model that E2 acts on ERα/βMeA neurons to provide bidirectional regulation of body weight and resistance to DIO. Disclosure H.Ye: None. M.Mun: None. Y.He: None. P.Xu: None. B.Feng: None. P.Luo: None. L.Carrillo-sáenz: None. V.C.Torres irizarry: None. L.Ibrahimi: None. N.Antony: None. M.Kota: None. D.Dixit: None. Funding National Institutes of Health (R01DK123098, P30DK020595, P20GM135002, R01DK129548, T32AA026577, K01DK119471); U.S. Department of Agriculture (3092-51000-062-04(B)S); American Heart Association (915789, 19CDA34660335, 20POST35120600); U.S. Department of Defense (W81XWH-20-1-0075)

1674-P: Increased Glucose Uptake in Brown Fat Promotes Energy Expenditure

Brown and beige fat dissipate energy as heat in response to β3-adrenergic receptor (β3AR) stimulation. Strategies to facilitate this response may be employed to promote weight loss and improve health in patients with metabolic disease. Previously, we discovered that GTPase RalA and its GAP complex RalGAP regulate exocytosis of glucose transporter GLUT4. We demonstrated in vivo, that adipose-tissue specific knockout of RalGAP subunit RalGAPB activates RalA and increases glucose uptake 7 times in brown fat (BAT), leading to improved glucose handling on high fat diet (HFD). Here we seek to test the effect of increased glucose uptake in BAT on energy expenditure (EE), using mice with BAT-specific knockout of RalGAPB (the KO mice). After 8 weeks on 45% HFD, the KO mice and control littermates (Ctr) were injected with β3AR agonist CL-316,243 (CL) or PBS for 8 days. Mice assigned to CL were placed in metabolic cages. Respiratory quotient was increased in the KO mice, indicating increased glucose oxidation (likely by BAT, due to increased glucose uptake). EE at room temperature was elevated in the KO mice. This was compensated by increased food uptake, explaining similar body weights between the KO and Ctr mice. CL injections, as expected, induced spikes in EE. Acute response to CL (arbitrarily defined as EE during 2 hours after CL injection) was consistent between daily CL injections in Ctr mice, and was increased twice in the KO mice compared to Ctr. In Ctr mice, 1st CL injection increased average day and night EE; this response gradually declined with consecutive CL injections. In the KO mice, 1st CL injection elicited similar to Ctr mice increase in average day and night EE; and the response to consecutive CL injections was preserved. As anticipated, CL reduced adiposity in Ctr mice, which was further augmented in the KO mice, consistent with finding on EE. We will further test the role of increased glucose uptake by BAT in EE of the KO mice, and will determine the mechanism of sustained CL responsiveness in the KO mice. Disclosure F.Rezayat: None. J.A.Resnick: None. I.M.Farah: None. Y.Skorobogatko: None. A.Saltiel: Board Member; Elgia Therapeutics. Funding National Institutes of Health (P30DK063491)

Hypermetabolism in mice carrying a near-complete human chromosome 21.

The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.

Dietary cysteine drives body fat loss via FMRFamide signaling in Drosophila and mouse

Obesity imposes a global health threat and calls for safe and effective therapeutic options. Here, we found that protein-rich diet significantly reduced body fat storage in fruit flies, which was largely attributed to dietary cysteine intake. Mechanistically, dietary cysteine increased the production of a neuropeptide FMRFamide (FMRFa). Enhanced FMRFa activity simultaneously promoted energy expenditure and suppressed food intake through its cognate receptor (FMRFaR), both contributing to the fat loss effect. In the fat body, FMRFa signaling promoted lipolysis by increasing PKA and lipase activity. In sweet-sensing gustatory neurons, FMRFa signaling suppressed appetitive perception and hence food intake. We also demonstrated that dietary cysteine worked in a similar way in mice via neuropeptide FF (NPFF) signaling, a mammalian RFamide peptide. In addition, dietary cysteine or FMRFa/NPFF administration provided protective effect against metabolic stress in flies and mice without behavioral abnormalities. Therefore, our study reveals a novel target for the development of safe and effective therapies against obesity and related metabolic diseases.

Preventing high-fat diet-induced obesity and related metabolic disorders by hydrodynamic transfer of Il-27 gene.

Interleukin-27 (IL-27) is a multifaceted heterodimer cytokine that exerts both pro-inflammatory and anti-inflammatory effects under different physiological conditions. IL-27 signaling plays a role in promoting energy expenditure through enhanced thermogenesis. The objective of the study is to determine the functional role of IL-27 in regulating weight gain, and glucose and lipid homeostasis in mice fed a high-fat diet (HFD). C57BL/6 mice were hydrodynamically transferred with pLIVE-IL-27 plasmids to achieve elevated level of IL-27 in blood and then kept on a HFD for 8 weeks. The impacts of Il-27 gene transfer on HFD-induced weight gain, adiposity, hepatic lipid accumulation, insulin resistance, glucose homeostasis and the mRNA levels of genes responsible for lipogenesis, glucose homeostasis and proinflammation were assessed by methods of biochemistry, histology, and molecular biology. Hydrodynamic gene transfer of Il-27 gene resulted in a peak level of serum IL-27 in mice at 14.5 ng/ml 24 h after gene transfer followed by a sustained level at 2 ng/ml. The elevated level of IL-27 blocked HFD-induced fat accumulation and weight gain without reducing food intake. It also prevented metabolic abnormities of liver steatosis and insulin resistance. IL-27 overexpression promoted expression of major thermogenic genes in brown adipose tissues; and attenuated chronic inflammation and macrophage infiltration into white adipose tissues. The results demonstrate that regulation of IL-27 level could be an effective strategy for management of obesity and obesity-related metabolic diseases.

Is meteorin-like (Metrnl) a novel biomarker to distinguish patients with obstructive sleep apnea (OSA) and patients withOSA at vascular risk.

Metrnl, a newly discovered adipokine with significant expression in white adipose tissue, promotes energy expenditure and contributes to the development of cardiovascular disorders. Endocan is a surrogate marker for endothelial dysfunction and is linked to cardiovascular risk factors. Higher cardiovascular morbidity and mortality have been linked to obstructive sleep apnea (OSA). In this study, we investigated the potential of serum Metrnl and endocan as biomarkers to identify patients with OSA who are at increased cardiovascular risk and differentiate them from healthy controls. The study included the evaluation of serum levels of endocan and Metrnl in individuals with OSA and healthy controls. All participants underwent full polysomnography to evaluate their sleep, and carotid intima-media thickness (CIMT) was measured in each of them. Patients with OSA(n = 117) had considerably lower levels of Metrnl and significantly higher levels of endocanthan controls (n = 59). Once confounding factors were taken into account, both Metrnl and endocan were effective predictors of OSA. Additionally, the severity of OSA, as determined by the apnea-hypopnea index (AHI), was linked to Metrnl and endocan levels. The study also found a significant and independent inverse association between CIMT and Metrnl, along with a positive association with endocan after making multiple adjustments. Furthermore, there was a significant and independent connection between CIMT and AHI. Based on these findings, Metrnl and endocan have the potential to be valuable markers for identifying patients with OSA who are at increased risk of early vascular damage.

Gypenosides improved inflammatory status, insulin resistance and hepatic steatosis in obese C57BL/6J mice

This study investigated the effect of dietary gypenosides on inflammation, insulin resistance and hepatic steatosis in male obese C57BL/6J mice induced by feeding a high-fat diet (HFD) for 16 weeks. Treatment with 300 mg/kg BW/d gypenosides for eight weeks significantly reduced body weight gain, total plasma cholesterol and homeostasis model assessment-estimated insulin resistance (HOMA-IR) index in the obese mice compared with the control. Gypenosides also reduced the levels of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6 in both plasma and inguinal white adipocyte tissue. Moreover, gypenosides consumption alleviated hepatic steatosis and insulin resistance possibly by promoting energy expenditure through the AMPK signaling pathway and upregulating thermogenic genes in the brown and inguinal white adipocyte tissues. In addition, these metabolic changes were accompanied by an increased Akkermansia muciniphila abundance in the gut microbiota. The results suggest the health benefits of gypenosides intake in obese mice.

An insight into brown/beige adipose tissue whitening, a metabolic complication of obesity with the multifactorial origin.

Brown adipose tissue (BAT), a thermoregulatory organ known to promote energy expenditure, has been extensively studied as a potential avenue to combat obesity. Although BAT is the opposite of white adipose tissue (WAT) which is responsible for energy storage, BAT shares thermogenic capacity with beige adipose tissue that emerges from WAT depots. This is unsurprising as both BAT and beige adipose tissue display a huge difference from WAT in terms of their secretory profile and physiological role. In obesity, the content of BAT and beige adipose tissue declines as these tissues acquire the WAT characteristics via the process called "whitening". This process has been rarely explored for its implication in obesity, whether it contributes to or exacerbates obesity. Emerging research has demonstrated that BAT/beige adipose tissue whitening is a sophisticated metabolic complication of obesity that is linked to multiple factors. The current review provides clarification on the influence of various factors such as diet, age, genetics, thermoneutrality, and chemical exposure on BAT/beige adipose tissue whitening. Moreover, the defects and mechanisms that underpin the whitening are described. Notably, the BAT/beige adipose tissue whitening can be marked by the accumulation of large unilocular lipid droplets, mitochondrial degeneration, and collapsed thermogenic capacity, by the virtue of mitochondrial dysfunction, devascularization, autophagy, and inflammation.

The combined effect of metformin and mirabegron on diet-induced obesity.

Anti-obesity medications act by suppressing energy intake (EI), promoting energy expenditure (EE), or both. Metformin (Met) and mirabegron (Mir) cause weight loss by targeting EI and EE, respectively. However, anti-obesity effects during concurrent use of both have yet to be explored. In this study, we investigated the anti-obesity effects, metabolic benefits, and underlying mechanisms of Met/Mir combination therapy in two clinically relevant contexts: the prevention model and the treatment model. In the prevention model, Met/Mir caused further 12% and 14% reductions in body weight (BW) gain induced by a high-fat diet compared to Met or Mir alone, respectively. In the treatment model, Met/Mir additively promoted 17% BW loss in diet-induced obese mice, which was 13% and 6% greater than Met and Mir alone, respectively. Additionally, Met/Mir improved glucose tolerance and insulin sensitivity. These benefits of Met/Mir were associated with increased EE, activated brown adipose tissue thermogenesis, and white adipose tissue browning. Significantly, Met/Mir did not cause cardiovascular dysfunction in either model. Together, the combination of Met and Mir could be a promising approach for the prevention and treatment of obesity by targeting both EI and EE simultaneously.

Anti-Obesity Effects of Metformin: A Scoping Review Evaluating the Feasibility of Brown Adipose Tissue as a Therapeutic Target.

Brown adipose tissue (BAT) is increasingly recognized as the major therapeutic target to promote energy expenditure and ameliorate diverse metabolic complications. There is a general interest in understanding the pleiotropic effects of metformin against metabolic complications. Major electronic databases and search engines such as PubMed/MEDLINE, Google Scholar, and the Cochrane library were used to retrieve and critically discuss evidence reporting on the impact of metformin on regulating BAT thermogenic activity to ameliorate complications linked with obesity. The summarized evidence suggests that metformin can reduce body weight, enhance insulin sensitivity, and improve glucose metabolism by promoting BAT thermogenic activity in preclinical models of obesity. Notably, this anti-diabetic agent can affect the expression of major thermogenic transcriptional factors such as uncoupling protein 1 (UCP1), nuclear respiratory factor 1 (NRF1), and peroxisome-proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) to improve BAT mitochondrial function and promote energy expenditure. Interestingly, vital molecular markers involved in glucose metabolism and energy regulation such as AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21) are similarly upregulated by metformin treatment in preclinical models of obesity. The current review also discusses the clinical relevance of BAT and thermogenesis as therapeutic targets. This review explored critical components including effective dosage and appropriate intervention period, consistent with the beneficial effects of metformin against obesity-associated complications.

Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis.

Psoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels. The therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action. Ncs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions. Taken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.

Rhamnose Displays an Anti-Obesity Effect Through Stimulation of Adipose Dopamine Receptors and Thermogenesis.

The imbalance between energy intake and energy expenditure leads to the prevalence of obesity worldwide. A strategy to simultaneously limit energy intake and promote energy expenditure would be an important new obesity treatment. Here, we identified rhamnose as a nonnutritive sweetener to promote adipose thermogenesis and energy expenditure. Rhamnose promotes cAMP production and PKA activation through dopamine receptor D1 in adipose tissue. As a result, rhamnose administration promotes UCP1-dependent thermogenesis and ameliorates obesity in mice. Thus, we have demonstrated a rhamnose-dopamine receptor D1-PKA axis critical for thermogenesis, and that rhamnose may have a role in therapeutic molecular diets against obesity.

Dietary selenomethionine attenuates obesity by enhancing beiging process in white adipose tissue

Imbalanced nutrient intake causes abnormal energy metabolism, which results in obesity. There is feasible evidence that selenium-rich (Se-rich) foods may alleviate obesity and enhance general public health, but the underlying mechanisms remain elusive. Herein we examined the effect of Se supplementation on white adipose tissue beiging process. The mice were fed with a normal diet or a Se-deficient high-fat diet (DHFD) until significant differences in terms of body weight, glucose tolerance and insulin sensitivity. Next, mice in the DHFD group were changed to a high-fat diet (HFD) containing specified amounts of selenomethionine (SeMet) (0, 150, 300, and 600 μg/kg) and continued to feed for 14 weeks. Notably, 150 μg/kg SeMet supplement highly protected mice from DHFD-induced obesity, insulin resistance, and lipid deposits in the liver and kidney, and featured by the enhanced beiging process in white adipose tissue and increased energy expenditure. Moreover, upon cold challenge, 150 μg/kg SeMet supplement enhanced cold tolerance in mice by inducing adipose beiging to promote energy expenditure, as evidenced by the increased expression of uncoupling protein-1 (UCP1) in adipocytes. Similarly, SeMet (10 μM) promoted the differentiation of beige adipocytes from the stromal vascular fraction. Collectively, our data support that optimal supplementation of SeMet could enhance the beiging process to attenuate HFD-induced obesity, which provides new insights into the relationship between dietary SeMet and type 2 diabetes.

Brown Adipose Tissue Sheds Extracellular Vesicles That Carry Potential Biomarkers of Metabolic and Thermogenesis Activity Which Are Affected by High Fat Diet Intervention.

Brown adipose tissue (BAT) is a key target for the development of new therapies against obesity due to its role in promoting energy expenditure; BAT secretory capacity is emerging as an important contributor to systemic effects, in which BAT extracellular vesicles (EVs) (i.e., batosomes) might be protagonists. EVs have emerged as a relevant cellular communication system and carriers of disease biomarkers. Therefore, characterization of the protein cargo of batosomes might reveal their potential as biomarkers of the metabolic activity of BAT. In this study, we are the first to isolate batosomes from lean and obese Sprague–Dawley rats, and to establish reference proteome maps. An LC-SWATH/MS analysis was also performed for comparisons with EVs secreted by white adipose tissue (subcutaneous and visceral WAT), and it showed that 60% of proteins were exclusive to BAT EVs. Precisely, batosomes of lean animals contain proteins associated with mitochondria, lipid metabolism, the electron transport chain, and the beta-oxidation pathway, and their protein cargo profile is dramatically affected by high fat diet (HFD) intervention. Thus, in obesity, batosomes are enriched with proteins involved in signal transduction, cell communication, the immune response, inflammation, thermogenesis, and potential obesity biomarkers including UCP1, Glut1, MIF, and ceruloplasmin. In conclusion, the protein cargo of BAT EVs is affected by the metabolic status and contains potential biomarkers of thermogenesis activity.

Purification of Egg White Lysozyme Determines the Downstream Fibrillation of Protein and Co-assembly with Phytochemicals to Form Edible Hydrogels Regulating the Lipid Metabolism.

Although the synthetic chemistry or synthetic biological systems have already shown the power of biomaterials engineering, natural bioresource matter is still a valuable library of raw ingredients for the production of biomaterials, in particular, the edible ones. However, the influence of upstream isolation and purification of the raw materials on their performance in the downstream processing procedures is still unexplored, which is essential for the engineering of biomaterials. Based on the comparison of conventional techniques, heating-induced precipitation combined with resin-blending ion exchange was developed as a simple and cheap method for the utilization of egg whites to produce the lysozyme that is found to be exclusively feasible for fibrillation. Even with similar purities, only the lysozyme prepared by this method could be utilized to form ordered linear aggregate fibrils. Fibrillation was recently pursued as a new approach to utilize bioresource mass for high-tech end-products. Phytochemicals, totally replacing salts, induced the lysozyme fibrils to form hydrogels spontaneously, which was further demonstrated in an in vivo study to prevent obesity induced by a high-fat diet (HFD) by reducing lipid absorption and lipogenesis, promoting energy expenditure, and inhibiting inflammation. The agri-food bioresource was successfully employed as a proof of concept in edible biomedical materials for the regulation of lipid metabolism.

The gene knockout of angiotensin II type 1a receptor improves high-fat diet-induced obesity in rat via promoting adipose lipolysis.

AimsThe renin-angiotensin system (RAS) is over-activated and the serum angiotensin II (Ang II) level increased in obese patients, while their correlations were incompletely understood. This study aims to explore the role of Ang II in diet-induced obesity by focusing on adipose lipid anabolism and catabolism.MethodsRat model of AT1aR gene knockout were established to investigate the special role of Ang II on adipose lipid metabolism. Wild-type (WT) and AT1aR gene knockout (AT1aR-/-) SD rats were fed with normal diet or high-fat diet for 12 weeks. Adipose morphology and adipose lipid synthesis and lipolysis were examined.ResultsAT1aR deficiency activated lipolysis-related enzymes and increased the levels of NEFAs and glycerol released from adipose tissue in high-fat diet rats, while did not affect triglycerides synthesis. Besides, AT1aR knockout promoted energy expenditure and fatty acids oxidation in adipose tissue. cAMP levels and PKA phosphorylation in the adipose tissue were significantly increased in AT1aR-/- rats fed with high-fat. Activated PKA could promote adipose lipolysis and thus improved adipose histomorphology and insulin sensitivity in high-fat diet rats.ConclusionsAT1aR deficiency alleviated adipocyte hypertrophy in high-fat diet rats by promoting adipose lipolysis probably via cAMP/PKA pathway, and thereby delayed the onset of obesity and related metabolic diseases.

Cross-Talk Between Gut Microbiota and Adipose Tissues in Obesity and Related Metabolic Diseases.

The rapid increase of obesity and associated diseases has become a major global health problem. Adipose tissues are critical for whole-body homeostasis. The gut microbiota has been recognized as a significant environmental factor in the maintenance of energy homeostasis and host immunity. A growing body of evidence suggests that the gut microbiota regulates host metabolism through a close cross-talk with adipose tissues. It modulates energy expenditure and alleviates obesity by promoting energy expenditure, but it also produces specific metabolites and structural components that may act as the central factors in the pathogenesis of inflammation, insulin resistance, and obesity. Understanding the relationship between gut microbiota and adipose tissues may provide potential intervention strategies to treat obesity and associated diseases. In this review, we focus on recent advances in the gut microbiota and its actions on adipose tissues and highlight the joint actions of the gut microbiota and adipose tissue with each other in the regulation of energy metabolism.

Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes.

For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance.

1314-P: Activating GABAergic Neurons in the Caudal Preoptic Area Promote Energy Expenditure in Diet-Induced Obesity

Obesity results from the imbalance between energy intake and energy expenditure, which are tightly regulated by dynamic hypothalamic circuits. Our goal is to identify and leverage hypothalamic components that promote energy expenditure for successful weight loss. Vesicular communication by ventromedial hypothalamic nucleus (VMN) steroidogenic factor 1 (Sf1) neurons is required for maintaining body weight, due at least in part to stimulating metabolic activity in adipose tissue, but the mechanistic details are unclear. VMNSf1 neurons efferently communicate with relatively few places in the brain but the most prominent projections are in the most caudal regions of the preoptic area (cPOA) (+0.1 to -0.3mm bregma, lateral to the suprachiasmatic nucleus) . We tested the hypothesis that GABAergic cPOA neurons promote energy expenditure and weight loss by activating either GABAergic or glutamatergic neurons via hM3dq, using vGATCre (vesicular GABAergic transporter) or vGLUT2Cre (vesicular glutamatergic transporter 2) in diet-induced obese male mice. Activating vGATcPOA neurons reduced body weight and adiposity without altering food intake. Activating vGLUT2cPOA neurons reduced body weight and food intake but did not reduce adiposity. Activating vGLUT2cPOA neurons reduced core body temperature, but not vGATcPOA neurons. We are currently investigating the mechanisms for how vGATcPOA neurons reduce adiposity. Weight loss is not likely mediated by direct inhibition of vGLUT2cPOA neurons because diet induced obese male mice with CNO-initiated signaling of hM4di in vglut2cPOA neurons does not reduce adiposity or body weight. Alternatively, vGATcPOA neurons may communicate with a distinct efferent system. Indeed, vGATcPOA, but not vGLUT2cPOA, neurons project to the lateral hypothalamus and medial raphe. Future studies will reveal the functional connection between VMNSf1 neurons and vGATcPOA neurons, and the descending circuitry that promotes energy expenditure. Disclosure R.Basu: None. A.J.Elmendorf: Research Support; Eli Lilly and Company. C.A.Mahler: Stock/Shareholder; AstraZeneca, Pfizer Inc. J.Flak: Research Support; Eli Lilly and Company. Funding American Diabetes Association (17-INI-15) ; IU CDMD NIH/NIDDK (P30 DK097512)

1375-P: Effects of Irisin Administration on Pancreatic Islets of Diabetic Mice

Irisin is a hormone secreted by skeletal muscle following exercise or excess of saturated fatty acids (SFAs) , able to improve metabolic homeostasis and promote energy expenditure. Serum irisin levels are reduced in type 2 diabetes (T2D) , while exogenous irisin administration improves glycemic control in diabetic mice. We have previously demonstrated that irisin protects human and rodent β-cells and pancreatic islets from SFAs-induced apoptosis, increases insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) , and promotes β-cell proliferation, both in vitro and in vivo in healthy wild-type mice. Irisin may also restore the defective GSIS and reduce the high rate of apoptosis that are characteristic of islets from T2D patients. However, the β-cellular effects of irisin administration to diabetic mice are still unknown. 6 weeks-old C57Bl/6 mice (n = 8) were fed a high-fat diet (HFD, 60% of energy deriving from fat) for weeks and then intraperitoneally injected with streptozotocin (STZ, 100 mg/Kg) to induce diabetes. 4 standard diet (SD) -fed mice were used as control. HFD/STZ mice were then treated with 0.5 μg/g irisin (n = 4) or vehicle (n = 4) for 14 days. Glucose tolerance, glycemia, insulinemia, body weight, pancreatic islet architecture and function were assessed throughout the study. As expected, compared to SD mice, HFD/STZ mice showed higher glycemia and body weight, glucose intolerance, and reduced GSIS; in addition, HFD/STZ mice showed reduced islet volume (-78%) , β-cell area (-35%) , and insulin content (-60%) , while increased α-cell area (+54%) . Irisin administration significantly restored glycemia (-31%) , body weight (-13%) , glucose tolerance (-27%, AUC) , GSIS (+23%, AUC) , islet volume (+61%) , β-cell (+34%) and α-cell (-49%) areas, and insulin content (+36%) . Of note, irisin treatment induced a 9-fold increase in β-cell proliferation rate. These results show for the first time that irisin can restore β-cell functional mass when administered in vivo to diabetic mice. Disclosure N.Marrano: None. G.Biondi: None. A.Borrelli: None. L.Roberto: None. A.Cignarelli: None. S.Perrini: None. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi. Funding EU – ESF PON R&I 2014-20, AIM