Regulation Of Energy Homeostasis Research Articles

Metformin activates AMPK and mTOR to Inhibit RANKL-stimulated osteoclast formation.

Metformin is a medication used to treat type 2 diabetes by inhibiting hepatic glucose production through adenosine monophosphate-activated protein kinase (AMPK) activation. Autophagy is closely related to the homeostasis and stress mechanisms of the body. In recent years, much research has arisen on therapeutic methods utilizing autophagy mechanisms to treat diagnoses such as metabolic diseases, tumors, and Alzheimer's disease. This study thus aimed to investigate the effects of metformin treatment on the differentiation of osteoclasts and changes in AMPK mechanisms, which play an important role in regulating energy homeostasis, and mTOR, a highly conserved kinase that regulates autophagy. Experimentation, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, tartrate-resistant acid phosphate (TRAP) staining, pit formation assay, immunofluorescence, western blotting, and real-time polymerase chain reaction (PCR) was performed to investigate the effects of metformin on osteoclast differentiation. Additionally, to investigate its association with AMPK and pathways, the AMPK inhibitor compound C and mammalian targets of rapamycin (mTOR) activator leucine were used to examine the expression of osteoclast- or autophagy-related proteins, genes, and TRAP-positive cells. Metformin showed no cytotoxic effects on mouse osteoblastic cell lines (MC3T3-E1) and murine macrophage cell lines (RAW264.7) but did inhibit osteoclast differentiation. Furthermore, metformin was found to inhibit osteoclast differentiation through AMPK activation and mTOR inhibition. In turn, AMPK inhibition using compound C promoted osteoclast differentiation, and mTOR activation using leucine inhibited autophagy and osteoclast differentiation. Metformin activates the AMPK pathway while functioning as an activator of mTOR, thereby leading to the inhibition of autophagy and osteoclast differentiation.

Novel targets of β-TrCP cooperatively accelerate carbohydrate and fatty acid consumption.

Cellular energy is primarily produced from glucose and fat through glycolysis and fatty acid oxidation (FAO) followed by the tricarboxylic acid cycle in mitochondria; energy homeostasis is carefully maintained via numerous feedback pathways. In this report, we uncovered a new master regulator of carbohydrate and lipid metabolism. When ubiquitin E3 ligase β-TrCP2 was inducibly knocked out in β-TrCP1 knockout adult mice, the resulting double knockout mice (DKO) lost fat mass rapidly. Biochemical analyses of the tissues and cells from β-TrCP2 KO and DKO mice revealed that glycolysis, FAO, and lipolysis were dramatically upregulated. The absence of β-TrCP2 increased the protein stability of metabolic rate-limiting enzymes including 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1A (CPT1A), and carnitine/acylcarnitine translocase (CACT). Our data suggest that β-TrCP is a potential regulator for total energy homeostasis by simultaneously controlling glucose and fatty acid metabolism and that targeting β-TrCP could be an effective strategy to treat obesity and other metabolic disorders.

Serum Myonectin and Adropin Levels in Predicting Diabetes

Introduction: Myonectin is a myokine associated with type 2 diabetes mellitus and insulin resistance, and adropin is a peptide hormone that prevents IR and impaired glucose tolerance. Adropin is produced by the liver and regulates energy homeostasis. This research aimed to examine the serum levels of myonectin and adropin levels among prediabetes, newly-diagnosed type 2 diabetes mellitus, and healthy controls.
 Methods: For this cross-sectional study, a total of 167 individuals were divided into 3 subgroups using OGTT and HbA1c; 61 prediabetes (36.5%), 62 nT2DM (37.1%), and 44 healthy controls (26.3%). Serum levels of myonectin and adropin were assayed using enzyme-linked immunoassay kits. The anthropometric (age, gender, weight, height, waist/hip ratio -WHR-, waist and hip circumference, and body mass index -BMI-) and biochemistry findings of the participants were evaluated between the groups.
 Results: Our study showed that myonectin levels are associated with nT2DM and WHR (p = 0.028 and p = 0.015, respectively). The serum levels of myonectin are significantly correlated with systolic blood pressure values in the prediabetes group (p = 0.017). Linear regression analysis revealed that nT2DM affects the serum levels of myonectin, but not adropin values. The adropin levels are correlated with LDL-cholesterol, total cholesterol, and triglyceride levels in the nT2DM group (p = 0.002, p= 0.004, and p = 0.035, respectively).
 Conclusion: The findings of the previous studies are supported by those of this study and indicated that the serum levels of myonectin may be associated with newly-diagnosed T2DM patients. Serum myonectin levels could be a valuable marker for predicting diabetes mellitus.

Altered function of arcuate leptin receptor expressing neuropeptide Y neurons depending on energy balance

ObjectiveOne of leptin's main targets in the hypothalamus are neuropeptide Y (NPY) neurons, with selective deletion of leptin receptors (Lepr) specifically in Npy neurons resulting in major alterations of energy partitioning between fat and bone mass. However, the specific action of these Npy+/Lepr+ neurons compared to Npy-negative Lepr (Npy−/Lepr+) neurons in regard to energy homeostasis regulation is unknown. MethodsSpecific AAV viral vectors were generated using DREADD and INTRSECT technology and used in male LeprCre/+ and LeprCre/+;NpyFlp/+ mice to assess the effect of activating either all Lepr neurons or specifically Npy+/Lepr+ or Npy−/Lepr+ neurons only on feeding, energy homeostasis control, and body composition. ResultsSelective stimulation of Npy+/Lepr+ neurons led to an immediate decrease in respiratory quotient followed by a delayed increase in food intake in standard chow fed, but interestingly not in high fat diet (HFD) fed mice. In addition, stimulation of Npy+/Lepr+ neurons led to a robust increase in brown adipose tissue thermogenesis and improved glucose tolerance. These effects were not observed in standard chow fed mice when Npy−/Lepr+ expressing neurons were specifically activated, suggesting the effects of leptin on these parameters are driven by NPY. However, under HFD condition when leptin levels are elevated, the stimulation of the Npy−/Lepr+ neurons increased food intake, physical activity and energy expenditure. Interestingly, chronic stimulation of Npy-positive Lepr neurons was able to increase bone mass independently of bodyweight, whilst chronic stimulation of the Npy−/Lepr+ neurons resulted in increased bodyweight and fat mass with proportionate increases in bone mass. ConclusionsTogether, these data indicate that leptin signalling through Npy-positive Lepr-expressing neurons controls energy partitioning via stimulation of thermogenesis, energy expenditure, and the use of fat as a fuel source. However, under prolonged HFD, leptin resistance may occur and actions of leptin signalling through Npy-negative Lepr hypothalamic neurons may exacerbate excess food intake.

Circadian Dysfunction in Adipose Tissue: Chronotherapy in Metabolic Diseases.

Essential for survival and reproduction, the circadian timing system (CTS) regulates adaptation to cyclical changes such as the light/dark cycle, temperature change, and food availability. The regulation of energy homeostasis possesses rhythmic properties that correspond to constantly fluctuating needs for energy production and consumption. Adipose tissue is mainly responsible for energy storage and, thus, operates as one of the principal components of energy homeostasis regulation. In accordance with its roles in energy homeostasis, alterations in adipose tissue's physiological processes are associated with numerous pathologies, such as obesity and type 2 diabetes. These alterations also include changes in circadian rhythm. In the current review, we aim to summarize the current knowledge regarding the circadian rhythmicity of adipogenesis, lipolysis, adipokine secretion, browning, and non-shivering thermogenesis in adipose tissue and to evaluate possible links between those alterations and metabolic diseases. Based on this evaluation, potential therapeutic approaches, as well as clock genes as potential therapeutic targets, are also discussed in the context of chronotherapy.

Oligofructose improves small intestinal lipid-sensing mechanisms via alterations to the small intestinal microbiota

BackgroundUpper small intestinal dietary lipids activate a gut-brain axis regulating energy homeostasis. The prebiotic, oligofructose (OFS) improves body weight and adiposity during metabolic dysregulation but the exact mechanisms remain unknown. This study examines whether alterations to the small intestinal microbiota following OFS treatment improve small intestinal lipid-sensing to regulate food intake in high fat (HF)-fed rats.ResultsIn rats fed a HF diet for 4 weeks, OFS supplementation decreased food intake and meal size within 2 days, and reduced body weight and adiposity after 6 weeks. Acute (3 day) OFS treatment restored small intestinal lipid-induced satiation during HF-feeding, and was associated with increased small intestinal CD36 expression, portal GLP-1 levels and hindbrain neuronal activation following a small intestinal lipid infusion. Transplant of the small intestinal microbiota from acute OFS treated donors into HF-fed rats also restored lipid-sensing mechanisms to lower food intake. 16S rRNA gene sequencing revealed that both long and short-term OFS altered the small intestinal microbiota, increasing Bifidobacterium relative abundance. Small intestinal administration of Bifidobacterium pseudolongum to HF-fed rats improved small intestinal lipid-sensing to decrease food intake.ConclusionOFS supplementation rapidly modulates the small intestinal gut microbiota, which mediates improvements in small intestinal lipid sensing mechanisms that control food intake to improve energy homeostasis.7qHK-ay1HXaqfvyHrZSPZbVideo

Hypothalamic astrocytic-BMAL1 regulates energy homeostasis in a sex-dependent manner

Here, we demonstrate that hypothalamic astrocytic BMAL1 computes cyclic metabolic information to optimize energetic resources in a sexually dimorphic manner. Knockdown of BMAL1 in female astrocytes leads to negative energy balance and alters basal metabolic cycles without affecting circadian locomotor activity. Thus, astrocytic BMAL1 contributes to the control of energy balance through the modulation of the metabolic rate, hepatic and white adipose tissue lipogenesis, and the activity of brown adipose tissue. Importantly, most of these alterations are specific to hypothalamic astrocytic BMAL1. Moreover, female mice with BMAL1 knockdown in astrocytes exhibited a "male-like" metabolic obese phenotype when fed a high-fat diet. Overall, our results suggest a sexually dimorphic effect of astrocytic BMAL1 on the regulation of energy homeostasis, which may be of interest in the physiopathology of obesity and related comorbidities.

The AMPK-dependent inhibition of autophagy plays a crucial role in protecting photoreceptor from photooxidative injury.

Excessive light exposure can potentially cause irreversible damage to the various photoreceptor cells, and this aspect has been considered as an important factor leading to the progression of the different retinal diseases. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are crucial intracellular signaling hubs involved in the regulation of cellular metabolism, energy homeostasis, cellular growth and autophagy. A number of previous studies have indicated that either AMPK activation or mTOR inhibition can promote autophagy in most cases. In the current study, we have established an in vitro as well as in vivo photooxidation-damaged photoreceptor model and investigated the possible influence of visible light exposure in the AMPK/mTOR/autophagy signaling pathway. We have also explored the potential regulatory effects of AMPK/mTOR on light-induced autophagy and protection achieved by suppressing autophagy in photooxidation-damaged photoreceptors. We observed that light exposure led to a significant activation of mTOR and autophagy in the photoreceptor cells. However, intriguingly, AMPK activation or mTOR inhibition significantly inhibited rather than promoting autophagy, which was termed as AMPK-dependent inhibition of autophagy. In addition, either indirectly suppressing autophagy by AMPK activation/ mTOR inhibition or directly blocking autophagy with an inhibitor exerted a significant protective effect on the photoreceptor cells against the photooxidative damage. Neuroprotective effects caused by the AMPK-dependent inhibition of autophagy were also verified with a retinal light injured mouse model in vivo. Overall, our findings demonstrated that AMPK / mTOR pathway could inhibit autophagy through AMPK-dependent inhibition of autophagy to significantly protect the photoreceptors from photooxidative injury, which may aid to further develop novel targeted retinal neuroprotective drugs.

Regulation of feeding and energy homeostasis by clock-mediated Gart in Drosophila

Feeding behavior is essential for growth and survival of animals; however, relatively little is known about its intrinsic mechanisms. Here, we demonstrate that Gart is expressed in the glia, fat body, and gut and positively regulates feeding behavior via cooperation and coordination. Gart in the gut is crucial for maintaining endogenous feeding rhythms and food intake, while Gart in the glia and fat body regulates energy homeostasis between synthesis and metabolism. These roles of Gart further impact Drosophila lifespan. Importantly, Gart expression is directly regulated by the CLOCK/CYCLE heterodimer via canonical E-box, in which the CLOCKs (CLKs) in the glia, fat body, and gut positively regulate Gart of peripheral tissues, while the core CLK in brain negatively controls Gart of peripheral tissues. This study provides insight into the complex and subtle regulatory mechanisms of feeding and lifespan extension in animals.

Exercise training induces depot-specific remodeling of protein secretion in skeletal muscle and adipose tissue of obese male mice.

Acute exercise induces changes in circulating proteins, which are known to alter metabolism and systemic energy balance. Skeletal muscle is a primary contributor to changes in the plasma proteome with acute exercise. An important consideration when assessing the endocrine function of muscle is the presence of different fiber types, which show distinct functional and metabolic properties and likely secrete different proteins. Similarly, adipokines are important regulators of systemic metabolism and have been shown to differ between depots. Given the health-promoting effects of exercise, we proposed that understanding depot-specific remodeling of protein secretion in muscle and adipose tissue would provide new insights into intertissue communication and uncover novel regulators of energy homeostasis. Here, we examined the effect of endurance exercise training on protein secretion from fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscle and visceral and subcutaneous adipose tissue. High-fat diet-fed mice were exercise trained for 6 wk, whereas a Control group remained sedentary. Secreted proteins from excised EDL and soleus muscle, inguinal, and epididymal adipose tissues were detected using mass spectrometry. We detected 575 and 784 secreted proteins from EDL and soleus muscle and 738 and 920 proteins from inguinal and epididymal adipose tissue, respectively. Of these, 331 proteins were secreted from all tissues, whereas secretion of many other proteins was tissue and depot specific. Exercise training led to substantial remodeling of protein secretion from EDL, whereas soleus showed only minor changes. Myokines released exclusively from EDL or soleus were associated with glycogen metabolism and cellular stress response, respectively. Adipokine secretion was completely refractory to exercise regulation in both adipose depots. This study provides an in-depth resource of protein secretion from muscle and adipose tissue, and its regulation following exercise training, and identifies distinct depot-specific secretion patterns that are related to the metabolic properties of the tissue of origin.NEW & NOTEWORTHY The present study examines the effects of exercise training on protein secretion from fast-twitch and slow-twitch muscle as well as visceral and subcutaneous adipose tissue of obese mice. Although exercise training leads to substantial remodeling of protein secretion from fast-twitch muscle, adipose tissue is completely refractory to exercise regulation.

Identification of GDF15 peptide fragments inhibiting GFRAL receptor signaling

Growth differentiation factor 15 (GDF15) is believed to be a major causative factor for cancer-induced cachexia. Recent elucidation of the central circuits involved in GDF15 function and its signaling through the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) has prompted the interest of targeting the GDF15-GFRAL signaling for energy homeostasis and body weight regulation. Here, we applied advanced peptide technologies to identify GDF15 peptide fragments inhibiting GFRAL signaling. SPOT peptide arrays revealed binding of GDF15 C-terminal peptide fragments to the extracellular domain of GFRAL. Parallel solid-phase peptide synthesis allowed for generation of complementary GDF15 peptide libraries and their subsequent functional evaluation in cells expressing the GFRAL/RET receptor complex. We identified a series of C-terminal fragments of GDF15 inhibiting GFRAL activity in the micromolar range. These novel GFRAL peptide inhibitors could serve as valuable tools for further development of peptide therapeutics towards the treatment of cachexia and other wasting disorders.

NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis

Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation.

Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons

Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.

Sympathetic circuits regulating hepatic glucose metabolism: where we stand.

The prevalence of metabolic disorders, including type 2 diabetes mellitus, continues to increase worldwide. Although newer and more advanced therapies are available, current treatments are still inadequate and the search for solutions remains. The regulation of energy homeostasis, including glucose metabolism, involves an exchange of information between the nervous systems and peripheral organs and tissues; therefore, developing treatments to alter central and/or peripheral neural pathways could be an alternative solution to modulate whole body metabolism. Liver glucose production and storage are major mechanisms controlling glycemia, and the autonomic nervous system plays an important role in the regulation of hepatic functions. Autonomic nervous system imbalance contributes to excessive hepatic glucose production and thus to the development and progression of type 2 diabetes mellitus. At cellular levels, change in neuronal activity is one of the underlying mechanisms of autonomic imbalance; therefore, modulation of the excitability of neurons involved in autonomic outflow governance has the potential to improve glycemic status. Tissue-specific subsets of preautonomic neurons differentially control autonomic outflow; therefore, detailed information about neural circuits and properties of liver-related neurons is necessary for the development of strategies to regulate liver functions via the autonomic nerves. This review provides an overview of our current understanding of the hypothalamus-ventral brainstem-liver pathway involved in the sympathetic regulation of the liver, outlines strategies to identify organ-related neurons, and summarizes neuronal plasticity during diabetic conditions with a particular focus on liver-related neurons in the paraventricular nucleus.

The ubiquitin-protein ligase MIEL1 localizes to peroxisomes to promote seedling oleosin degradation and lipid droplet mobilization

Lipid droplets are organelles conserved across eukaryotes that store and release neutral lipids to regulate energy homeostasis. In oilseed plants, fats stored in seed lipid droplets provide fixed carbon for seedling growth before photosynthesis begins. As fatty acids released from lipid droplet triacylglycerol are catabolized in peroxisomes, lipid droplet coat proteins are ubiquitinated, extracted, and degraded. In Arabidopsis seeds, the predominant lipid droplet coat protein is OLEOSIN1 (OLE1). To identify genes modulating lipid droplet dynamics, we mutagenized a line expressing mNeonGreen-tagged OLE1 expressed from the OLE1 promoter and isolated mutants with delayed oleosin degradation. From this screen, we identified four miel1 mutant alleles. MIEL1 (MYB30-interacting E3 ligase 1) targets specific MYB transcription factors for degradation during hormone and pathogen responses [D. Marino et al., Nat. Commun. 4, 1476 (2013); H. G. Lee and P. J. Seo, Nat. Commun. 7, 12525 (2016)] but had not been implicated in lipid droplet dynamics. OLE1 transcript levels were unchanged in miel1 mutants, indicating that MIEL1 modulates oleosin levels posttranscriptionally. When overexpressed, fluorescently tagged MIEL1 reduced oleosin levels, causing very large lipid droplets. Unexpectedly, fluorescently tagged MIEL1 localized to peroxisomes. Our data suggest that MIEL1 ubiquitinates peroxisome-proximal seed oleosins, targeting them for degradation during seedling lipid mobilization. The human MIEL1 homolog (PIRH2; p53-induced protein with a RING-H2 domain) targets p53 and other proteins for degradation and promotes tumorigenesis [A. Daks et al., Cells 11, 1515 (2022)]. When expressed in Arabidopsis, human PIRH2 also localized to peroxisomes, hinting at a previously unexplored role for PIRH2 in lipid catabolism and peroxisome biology in mammals.

Histaminergic regulation of food intake.

Histamine is a biogenic amine that acts as a neuromodulator within the brain. In the hypothalamus, histaminergic signaling contributes to the regulation of numerous physiological and homeostatic processes, including the regulation of energy balance. Histaminergic neurons project extensively throughout the hypothalamus and two histamine receptors (H1R, H3R) are strongly expressed in key hypothalamic nuclei known to regulate energy homeostasis, including the paraventricular (PVH), ventromedial (VMH), dorsomedial (DMH), and arcuate (ARC) nuclei. The activation of different histamine receptors is associated with differential effects on neuronal activity, mediated by their different G protein-coupling. Consequently, activation of H1R has opposing effects on food intake to that of H3R: H1R activation suppresses food intake, while H3R activation mediates an orexigenic response. The central histaminergic system has been implicated in atypical antipsychotic-induced weight gain and has been proposed as a potential therapeutic target for the treatment of obesity. It has also been demonstrated to interact with other major regulators of energy homeostasis, including the central melanocortin system and the adipose-derived hormone leptin. However, the exact mechanisms by which the histaminergic system contributes to the modification of these satiety signals remain underexplored. The present review focuses on recent advances in our understanding of the central histaminergic system's role in regulating feeding and highlights unanswered questions remaining in our knowledge of the functionality of this system.

Lipid droplets are versatile organelles involved in plant development and plant response to environmental changes.

Since decades plant lipid droplets (LDs) are described as storage organelles accumulated in seeds to provide energy for seedling growth after germination. Indeed, LDs are the site of accumulation for neutral lipids, predominantly triacylglycerols (TAGs), one of the most energy-dense molecules, and sterol esters. Such organelles are present in the whole plant kingdom, from microalgae to perennial trees, and can probably be found in all plant tissues. Several studies over the past decade have revealed that LDs are not merely simple energy storage compartments, but also dynamic structures involved in diverse cellular processes like membrane remodeling, regulation of energy homeostasis and stress responses. In this review, we aim to highlight the functions of LDs in plant development and response to environmental changes. In particular, we tackle the fate and roles of LDs during the plant post-stress recovery phase.

1670-P: Sex-Dependent Effects of PERK Deletion in Thermogenic Adipocytes

Brown and beige adipocytes dissipate chemical energy as heat through thermogenic respiration, thereby playing important roles in adaptive thermogenesis and energy homeostasis in mice. The Protein Kinase R (PKR)-Like Endoplasmic Reticulum Kinase (PERK) has been shown to be required for mitochondrial thermogenesis in cultured brown adipocytes, and in mice lacking PERK in white and brown adipose tissues. Here, we tested the hypothesis that PERK expression specifically in thermogenic adipocytes is required for adaptive thermogenesis and to regulate energy homeostasis in mice, by selectively deleting PERK in Ucp1-expressing cells (brown and beige adipocytes) of male and female mice. At baseline conditions, mitochondria oxygen consumption rates (OCR) were significantly reduced in brown adipocytes isolated from male, but not from female KO mice. After being housed at thermoneutrality for 7 days (30 °C), wild type (WT) and KO mice were exposed to 4 °C for 3 days. Surprisingly, both male and female KO mice were able to properly adapt to cold exposure, as demonstrated by preserved core body temperatures relative to WT mice. Interestingly, age-induced weight gain, fat mass expansion and impairments in glucose homeostasis were all attenuated in KO males, while weight gain was exacerbated in KO females. This correlated with increased energy expenditure (EE) in male mice, while EE was reduced in female mice. We, next, tested the hypothesis that male KO mice would be resistant to diet-induced obesity. After 12 weeks of high-fat feeding (60% calories from fat), male KO mice became as obese, glucose intolerant and insulin resistant as WT mice. In conclusion, our data suggest that PERK expression in thermogenic adipocytes reduces mitochondrial OCR in male mice, but is dispensable for thermoregulation after short-term cold exposure in both male and female mice. Furthermore, our data reveal a sex-dependent effect of PERK in thermogenic adipocytes in the regulation of energy homeostasis, which is dependent on changes in EE. Disclosure J.Jena: None. L.M.García-peña: None. R.Pereira: None. Funding National Institutes of Health (DK125405, 2T32DK112751-06)

301-OR: Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation

Brain estrogen receptor α (ERα) signaling plays a vital role in the regulation of energy homeostasis and adipose tissue metabolism. It has been demonstrated that ERα is abundantly expressed in the ventrolateral region of the ventromedial hypothalamus (vlVMH), a sex-dimorphic structure that directly modulates brown adipose tissue (BAT) thermogenesis. We previously showed that an ERαvlVMH-originated neural circuit responds to changes in ambient temperature and nutritional states, suggesting a potential role of this neural circuit in metabolic adaptation. Here, we found that chronic activation of ERαvlVMH neurons in male mice reduces body weight, decreases adiposity, and prevents diet-induced obesity (DIO), which is associated with increases in BAT thermogenesis and core temperature. Conversely, chronic inhibition of ERαvlVMH neurons increases body weight, promotes adiposity, and decreases baseline BAT temperature. Notably, ERαvlVMH neural inhibition also impairs cold-induced food consumption and BAT thermogenesis, resulting in lethal phenotypes during chronic cold exposure. Post hoc histology analysis further revealed that ERαvlVMH neural inhibition induces adipose tissue whitening. Finally, we explored the anatomical distribution of ERαvlVMH downstream neural circuitries. Anterograde tracing revealed ERαvlVMH-originated projections to the medial preoptic area (MPA), paraventricular nucleus (PVN), substantia nigra (SNR) and dorsal raphe nucleus (DRN). Interestingly, transsynaptic retrograde tracing further demonstrated that these brain regions send projections to inguinal white adipose tissue (iWAT), suggesting potential ERαvlVMH-originated circuits involved in adipose tissue adaptation. Together, these findings support a model that estrogens act through ERαvlVMH neurons to modulate fat-specific outputs and subsequently regulate adipose tissue adaptation to cold challenges. Disclosure V.C.Torres irizarry: None. P.Xu: None. H.Ye: None. P.Luo: None. L.Carrillo-sáenz: None. X.Yang: None. M.D.Munoz: None. N.Antony: None. Y.Jiang: None. Y.He: None. Funding National Institutes of Health (R01DK123098, T32AA026577); U.S. Department of Defense (W81XWH-19-PRMRP-DA); National Institute of Diabetes and Digestive and Kidney Diseases (DK020595); American Heart Association (915789)

1523-P: A Leptin-Mediated Interoceptive Network between the Brain and Brown Adipose Tissue

Obesity is attributed to chronic disruption in energy homeostasis. This phenomenon is controlled by systemic and local signals such as leptin, a nutrient-sensitive signal secreted primarily by the white adipose tissue (WAT). Previously, interscapular brown adipose tissue (iBAT) has been shown to express undetectable or very low levels of leptin. Unexpectedly, in this study, we observed that iBAT leptin expression displayed a distinct circadian pattern and fluctuated with nutritional and ambient temperature. These observations suggest a vital role of iBAT leptin in the regulation of energy homeostasis. To explore this idea, we performed gain and loss of function experiments by overexpressing (LEPOE) or knocking down (LEPKD) leptin selectively in UCP1+ cells of iBAT, respectively. We found that LEPOE reduced food intake while LEPKD increased it in normal and fasting-induced feeding conditions. Notably, LEPOE/LEPKD selectively increased/decreased the mRNA expression of leptin in the iBAT without affecting circulating leptin levels, indicating a possible paracrine role of iBAT leptin. In supporting this point of view, we found that the leptin receptor is highly expressed in the iBAT-associated sensory nerve (iBAT-SN). Moreover, iBAT-specific leptin infusion activated leptin signaling in the iBAT-SN and subsequently stimulated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Conversely, chemical ablation of iBAT-SN increased food intake and blunted hypothalamic POMC activation induced by iBAT-specific leptin infusion. These findings indicate that iBAT possesses a structural and functional basis for paracrine leptin signaling via iBAT-SN, which cross-talks with POMC neurons to modulate energy homeostasis. Our results support an unappreciated metabolic role of iBAT leptin in energy homeostasis. Disclosure M.D.Munoz: None. X.Yang: None. V.C.Torres irizarry: None. P.Luo: None. L.Carrillo-sáenz: None. N.Antony: None. C.Liew: None. P.Xu: None. Funding National Institutes of Health (R01DK123098); U.S. Department of Defense (W81XWH-19-PRMRP-DA); Diabetes Research and Training Center (DK020595)