Body Weight Homeostasis Research Articles

Adipocyte-Specific Ablation of PU.1 Promotes Energy Expenditure and Ameliorates Metabolic Syndrome in Aging Mice.

Objective: Although PU.1/Spi1 is known as a master regulator for macrophage development and function, we have reported previously that it is also expressed in adipocytes and is transcriptionally induced in obesity. Here, we investigated the role of adipocyte PU.1 in the development of the age-associated metabolic syndrome. Methods: We generated mice with adipocyte-specific PU.1 knockout, assessed metabolic changes in young and older adult PU.1fl/fl (control) and AdipoqCre PU.1fl/fl (aPU.1KO) mice, including body weight, body composition, energy expenditure, and glucose homeostasis. We also performed transcriptional analyses using RNA-Sequencing of adipocytes from these mice. Results: aPU.1KO mice have elevated energy expenditure at a young age and decreased adiposity and increased insulin sensitivity in later life. Corroborating these observations, transcriptional network analysis indicated the existence of validated, adipocyte PU.1-modulated regulatory hubs that direct inflammatory and thermogenic gene expression programs. Conclusion: Our data provide evidence for a previously uncharacterized role of PU.1 in the development of age-associated obesity and insulin resistance.

Berbamine reduces body weight via suppression of small GTPase Rab8a activity and activation of paraventricular hypothalamic neurons in obese mice

Small GTPase Rab8a is involved in fat-specific protein 27 (Fsp27) mediated lipid droplet accumulation in adipocytes. By screening inhibitors of Rab8a GTPase from a natural compound library, berbamine (BBM), a marketing drug for treatment of leukopenia in China, was identified to inhibit the activity of Rab8a GTPase and block the differentiation of 3T3-L1 adipocytes. Animal study showed that BBM could reduce body weight, improved glucose and lipid metabolic homeostasis in high-fat diet-induced obesity (DIO) C57BL/6 mice and db/db mice. Additional, BBM increased energy expenditure and inhibited food intake in mice but not in lean mice. Moreover, intracerebroventricular injection (i.c.v.) of BBM inhibited feeding behavior and increased c-Fos expression in paraventricular nucleus of the hypothalamus (PVH) of mice. Our data suggest that BBM may improve obesity through the inhibition of Rab8a GTPase activity and the activation of anorexigenic energy-sensing neuron in PVH.

Maternal obesity and ovarian failure: is leptin the culprit?

At the time of its discovery and characterization in 1994, leptin was mostly considered a metabolic hormone able to regulate body weight and energy homeostasis. However, in recent years, a great deal of literature has revealed leptin's pleiotropic nature, through its involvement in numerous physiological contexts including the regulation of the female reproductive tract and ovarian function. Obesity has been largely associated with infertility, and leptin signalling is known to be dysregulated in the ovaries of obese females. Hence, the disruption of ovarian leptin signalling was shown to contribute to the pathophysiology of ovarian failure in obese females, affecting transcriptional programmes in the gamete and somatic cells. This review attempts to uncover the underlying mechanisms contributing to female infertility associated with obesity, as well as to shed light on the role of leptin in the metabolic dysregulation within the follicle, the effects on the oocyte epigenome, and the potential long-term consequence to embryo programming.

Gestational Diabetes, Colorectal Cancer, Bariatric Surgery, and Weight Loss among Diabetes Mellitus Patients: A Mini Review of the Interplay of Multispecies Probiotics.

Diabetes mellitus has been steadily increasing over the past decades and is one of the most significant global public health concerns. Diabetes mellitus patients have an increased risk of both surgical and post-surgical complications. The post-surgical risks are associated with the primary condition that led to surgery and the hyperglycaemia per se. Gut microbiota seems to contribute to glucose homeostasis and insulin resistance. It affects the metabolism through body weight and energy homeostasis, integrating the peripheral and central food intake regulatory signals. Homeostasis of gut microbiota seems to be enhanced by probiotics pre and postoperatively. The term probiotics is used to describe some species of live microorganisms that, when administered in adequate amounts, confer health benefits on the host. The role of probiotics in intestinal or microbial skin balance after abdominal or soft tissue elective surgeries on DM patients seems beneficial, as it promotes anti-inflammatory cytokine production while increasing the wound-healing process. This review article aims to present the interrelation of probiotic supplements with DM patients undergoing elective surgeries.

Astrocytic lipid metabolism determines susceptibility to diet-induced obesity.

Hypothalamic astrocytes play pivotal roles in both nutrient sensing and the modulation of synaptic plasticity of hypothalamic neuronal circuits in control of feeding and systemic glucose and energy metabolism. Here, we show the relevance of astrocytic fatty acid (FA) homeostasis under the opposing control of angiopoietin-like 4 (ANGPTL-4) and peroxisome proliferator–activated receptor gamma (PPARγ) in the cellular adaptations of hypothalamic astrocytes and neurons to the changing metabolic milieu. We observed that increased availability of FA in astrocytes induced by cell- and time-selective knockdown of Angptl4 protected against diet-induced obesity, while cell- and time-selective knockdown of Angptl4-regulated Pparγ lead to elevated susceptibility to obesity. Overall, our results unravel a previously unidentified role for astrocytic FA metabolism in central control of body weight and glucose homeostasis.

The effect of sleeve ablation of gastric mucosa on body weight and glucose homeostasis in Sprague-Dawley rat model.

The gastric mucosa is an important endocrine organ, most of which is resected in sleeve gastrectomy (SG). The effect of removing most of the gastric mucosa has not been studied. To assess the effect of ablating the gastric mucosa (an area proportional to that in SG), on obesity and diabetes in a rat model. The Affiliated Hospital of Xuzhou Medical University in Xuzhou Jiangsu, P. R. China. Among 34 fatty Sprague-Dawley rats, 26 randomly received low-dose streptozotocin (STZ) to induce diabetes and then were randomly assigned to gastric mucosa ablation (GMA, n = 10), sleeve gastrectomy (SG, n = 8), and sham (n = 8) groups. The remaining normal fatty rats were assigned to the non-diabetic gastric mucosa ablation (nGMA, n = 8) group. In the GMA groups, the gastric mucosa was thermally ablated using electrocautery. Rats were followed for 8 weeks postoperatively. Preoperative oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and mixed meal tolerance test (MMTT) were repeated at designated time points postoperatively. Changes in body weight, food intake, and fasting blood glucose were also recorded. Fasting ghrelin concentration and area under curve (AUC) decreased significantly (P < .05) in the GMA groups and the SG group after surgery. Gastrin concentration remained unchanged in SG but decreased significantly in the GMA groups after surgery. Significantly increased GLP-1 AUC was found in the GMA groups and the SG group postoperatively. The decrease in fasting blood glucose did not differ significantly between the diabetic GMA and SG groups after surgery. Glucose AUC during OGTT in both SG and diabetic GMA groups was decreased significantly from the preoperative level, but the decreased glucose AUC in the SG group was significantly greater (P < .05). The decrease in body weight and food intake in the SG group was significantly greater than in the GMA groups. Ablation of most of the gastric mucosa along the greater curvature is effective in weight loss and glycemic control in a rodent model.

Reverse-translational identification of a cerebellar satiation network.

The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically-distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.

Abstract 8902: The High Circulating Leptin is Associated With Increased Mortality Risk in Stable Coronary Heart Disease Patients

Introduction: Leptin is an adipocyte-derived peptide, involved in energy homeostasis and regulation of body weight. The position of leptin in cardiovascular pathophysiology remained controversial, some studies suggest a detrimental effect of hyperleptinemia on the cardiovascular (CV) system, while others assume the role of leptin as protective. Hypothesis: We explore whether high leptin status affects the mortality/ morbidity risk in stable patients with coronary heart disease. Methods: 975 patients, ≥6 months after myocardial infarction (EUROASPIRE cohort) were followed in a prospective study. All-cause or CV death, non-fatal events (myocardial infarction, stroke or any revascularization) and hospitalizations for heart failure (HF) were registered as outcomes Results: High serum leptin concentrations (≥18.9 ng/mL, i.e. 4 th quartile) indicate inferior survival, as well as a higher incidence of fatal vascular event or hospitalizations for HF ( see Figure). Even after full adjustment for potential covariates, high leptin was associated with significantly increased 5-years risk of all-cause death [HRR 2.10 (95%CIs:1.29-3.42), p&lt;0.003], CV death [HRR 2.65 (95%CIs:1.48-4.74), p&lt;0.001] and HF hospitalization [HRR 1.95 (95%CIs:1.11-3.44), p&lt;0.020]. In contrast, the incidence risk of non-fatal CV events was only marginally and non-significantly influenced [HRR 1.27 (95%CIs:0.76-2.13), p=0.359] Conclusions: High leptin concentration entails an increased risk of mortality (apparently driven by fatal CV events) and future worsening of HF, on top of conventional CV risk factors and the baseline status of left ventricular function.

PRDM12 in Health and Diseases.

PRDM12 is a member of the PRDI-BF1 (positive regulatory domain I-binding factor 1) homologous domain (PRDM)-containing protein family, a subfamily of Kruppel-like zinc finger proteins, controlling key processes in the development of cancer. PRDM12 is expressed in a spatio-temporal manner in neuronal systems where it exerts multiple functions. PRDM12 is essential for the neurogenesis initiation and activation of a cascade of downstream pro-neuronal transcription factors in the nociceptive lineage. PRDM12 inactivation, indeed, results in a complete absence of the nociceptive lineage, which is essential for pain perception. Additionally, PRDM12 contributes to the early establishment of anorexigenic neuron identity and the maintenance of high expression levels of pro-opiomelanocortin, which impacts on the program bodyweight homeostasis. PRDMs are commonly involved in cancer, where they act as oncogenes/tumor suppressors in a “Yin and Yang” manner. PRDM12 is not usually expressed in adult normal tissues but its expression is re-activated in several cancer types. However, little information is currently available on PRDM12 expression in cancers and its mechanism of action has not been thoroughly described. In this review, we summarize the recent findings regarding PRDM12 by focusing on four main biological processes: neurogenesis, pain perception, oncogenesis and cell metabolism. Moreover, we wish to highlight the importance of future studies focusing on the PRDM12 signaling pathway(s) and its role in cancer onset and progression.

Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression

Simple SummaryVoltage-dependent potassium channels control the proliferation of mammalian cells. In addition, mitochondria physiology is highly dynamic during the cell cycle. The aim of this work was to investigate whether the Kv1.3 channel participates in the mitochondrial control of cell cycle progression. Our data confirmed that Kv1.3 facilitates the proliferation of preadipocytes through the control of mitochondrial dynamics. In addition, adipogenesis was also dependent on Kv1.3 expression. We shed light on the role of Kv1.3 in mitochondria and adipose tissue metabolism, contributing further to the control of cell proliferation by Kv1.3.The voltage-gated potassium channel Kv1.3 is a potential therapeutic target for obesity and diabetes. The genetic ablation and pharmacological inhibition of Kv1.3 lead to a lean phenotype in rodents. The mechanism of regulation of body weight and energy homeostasis involves Kv1.3 expression in different organs, including white and brown adipose tissues. Here, we show that Kv1.3 promotes the proliferation of preadipocytes through the control of mitochondrial dynamics. Kv1.3 is expressed in mitochondria exhibiting high affinity for the perinuclear population. The mitochondrial network is highly dynamic during the cell cycle, showing continuous fusion-fission events. The formation of a hyperfused mitochondrial network at the G1/S phase of the cell cycle is dependent on Kv1.3 expression. Our results demonstrate that Kv1.3 promotes preadipocyte proliferation and differentiation by controlling mitochondrial membrane potential and mitochondrial dynamics at the G1 phase of the cell cycle.

Abstract T6: Adipocyte Bardet-Biedl Syndrome 1 Gene Is Critical For Blood Pressure Regulation

Bardet-Biedl syndrome (BBS) proteins have emerged as critical regulators of various physiological functions including blood pressure. The presence of hypertension in BBS patients is consistent with the finding that BBS knockout mice exhibit increased renal sympathetic nerve activity and arterial pressure. However, the role and contribution of Bbs genes in various tissues such as adipose tissue to blood pressure regulation remains unclear. To address this, we generated a novel conditional knockout mouse that lacks the Bbs1 gene in adipocytes by breeding mice bearing floxed alleles of the Bbs1 gene (Bbs1 flox/flox ) with mice expressing Cre specifically in adipocytes (Adiponectin Cre mice). Cre-mediated recombination was verified by loss of Bbs1 expression in fat pads, but not in other tissues such as the kidneys, liver and skeletal muscle. Next, we assessed whether adipocyte Bbs1 gene deletion affects body weight and glucose homeostasis. Interestingly, no body weight phenotype was observed in both male and female Adipo Cre /Bbs1 flox/flox mice compared to their control littermates (males: 40.5±2.9 g vs 37.4±5.1 g; female: 27.7±4.0 g vs 27.5±3.6 g; 16 weeks old). However, insulin tolerance test uncovered impaired insulin-induced glucose clearance in both male and female Adipo Cre /Bbs1 flox/flox mice. Subsequently, we measured blood pressure and found that Adipo Cre /Bbs1 flox/flox mice have a remarkable increase in systolic blood pressure (130.4±11.2 mmHg) compared to the control littermates (119.1±4.5 mmHg, p &lt;0.05). Finally, measurement of the expression of the renin-angiotensin system components revealed significantly elevated angiotensinogen mRNA (2.43±1.31 AU vs 1±0.72 AU, p &lt;0.01) and angiotensin-converting enzyme mRNA (2.96±2.51 AU vs 1±0.95 AU, p &lt;0.05) in peri-renal adipose tissue, but not in other fat pads such as brown and inguinal adipose tissues. Interestingly, gene expression of angiotensin receptor 1a was not significantly altered by Bbs1 gene deletion. Taken together, our findings demonstrate that Bbs1 gene in adipose tissue play an important role in the control of insulin sensitivity and blood pressure.

Взаимосвязь между уровнем тиреотропного гормона, инсулинорезистентностью и сердечно-сосудистыми факторами риска у пациентов с ожирением и субклиническим гипотиреозом

Актуальность. Эпидемия избыточного веса и ожирения представляет собой серьезную проблему для системы здравоохранения во всем мире и требует проведения профилактических мероприятий. Предполагаемые взаимо­связи между гормонами щитовидной железы, массой тела и гомеостазом жировой ткани находятся в центре внимания нескольких исследований в последние годы, однако причинно-следственные связи между этими параметрами четко не установлены. Цель: изучить взаимосвязь между уровнем тиреотропного гормона (ТТГ), инсулинорезистентностью (ИР) и факторами риска сердечно-сосудистых заболеваний в выборке лиц с ожирением и субклиническим гипотиреозом. Материалы и методы. Проведен ретроспективный продольный анализ 145 лиц с ожирением. Проанализированы уровни ТТГ и свободного тироксина (свT4), антропометрические измерения и результаты лабораторных тестов. Результаты. У 23 человек уровень ТТГ был выше нормы (субклинический гипотиреоз). Окружность талии (ОТ) у них была достоверно выше, чем у людей в состоянии эутиреоза. Уровень ТТГ в сыворотке положительно коррелировал с индексом инсулинорезистентности (HOMA-IR), содержанием триглицеридов и холестерина липопротеинов высокой плотности (ЛПВП). С использованием ТТГ и индекса массы тела в качестве независимых переменных было показано, что уровни ТТГ независимо связаны с HOMA-IR (p = 0,002) и содержанием триглицеридов (p = 0,006). Среди эутиреоидных пациентов лица со значениями ТТГ &lt; 2,5 мМЕ/мл демонстрировали статистически значимое снижение соотношения ОТ и охвата бедер, уровня ЛПВП и показателей HOMA-IR, а также тенденцию к более низким значениям ОТ. Выводы. Субклинический гипотиреоз у людей с ожирением связан с избыточным наличием висцеральной жировой ткани. В настоящей выборке людей с ожирением уровни ТТГ связаны с инсулинорезистентностью.

Developmental genes controlling neural circuit formation are expressed in the early postnatal hypothalamus and cellular lining of the third ventricle.

The arcuate nucleus of the hypothalamus is central in the regulation of body weight homeostasis through its ability to sense peripheral metabolic signals and relay them, through neural circuits, to other brain areas, ultimately affecting physiological and behavioural changes. The early postnatal development of these neural circuits is critical for normal body weight homeostasis, such that perturbations during this critical period can lead to obesity. The role for peripheral regulators of body weight homeostasis, including leptin, insulin and ghrelin, in this postnatal development is well described, yet some of the fundamental processes underpinning axonal and dendritic growth remain unclear. Here, we hypothesised that molecules known to regulate axonal and dendritic growth processes in other areas of the developing brain would be expressed in the postnatal arcuate nucleus and/or target nuclei where they would function to mediate the development of this circuitry. Using state-of-the-art RNAscope® technology, we have revealed the expression patterns of genes encoding Dcc/Netrin-1, Robo1/Slit1 and Fzd5/Wnt5a receptor/ligand pairs in the early postnatal mouse hypothalamus. We found that individual genes had unique expression patterns across developmental time in the arcuate nucleus, paraventricular nucleus of the hypothalamus, ventromedial nucleus of the hypothalamus, dorsomedial nucleus of the hypothalamus, median eminence and, somewhat unexpectedly, the third ventricle epithelium. These observations indicate a number of new molecular players in the development of neural circuits regulating body weight homeostasis, as well as novel molecular markers of tanycyte heterogeneity.

Gutting out Myc to decrease ceramides.

MYC is a transcription factor controlling growth and nutrient metabolism. Luo et al. now link intestinal expression of MYC to impairments in glucose, lipid and body-weight homeostasis by uncovering novel roles of MYC in regulating the glucagon-like peptide GLP1 and the ceramide-biosynthesis regulator CERS4. Myc deletion in the intestinal epithelium prevents or reverses diet-induced obesity and hepatic steatosis in mice. Critically, people with obesity display elevated MYC and CERS4 expression in the ileum, thus further supporting the clinical relevance of these findings.

The possible role of biochanin A in ameliorating endoplasmic reticulum stress-induced leptin resistance.

Leptin plays an important role in energy intake and body weight homeostasis. Leptin is secreted mainly from white adipose tissue and circulates in the bloodstream, inhibiting food intake by activating the leptin receptor expressed on hypothalamic neurons. Recent studies have demonstrated leptin resistance as the main factor involved in the development of obesity. We and others have reported that leptin resistance is caused by endoplasmic reticulum (ER) stress due to the accumulation of unfolded protein in the ER. In the present study, we investigated whether isoflavones could affect ER stress and the subsequent development of leptin resistance. We showed that biochanin A, a family of isoflavones, strongly attenuated cell death induced by ER stress in neuronal cells, improved ER stress-induced impairments in leptin signaling, and suppressed ER stress-induced expression of glucose-regulated protein 78. These results suggest that biochanin A may have pharmacological properties that can ameliorate leptin resistance by reducing ER stress.

Progression of anorexia nervosa: An insight into neurological and biological mechanisms influencing the personality patterns of anorexics

Anorexia nervosa has emerged as a prominent eating disorder affecting young women. This disorder's fundamental characteristic is an abnormally low weight achieved by severe calorie restriction and refusal to maintain body weight at or above the minimally normal weight for age and height. It is a complex disorder with its origins still not explicitly defined. In anorexic individuals, an imbalance in the molecular signalling and hypothalamic neuropeptides is believed to be significantly responsible for alterations in the biological mechanisms associated with body weight, appetite and energy homeostasis. The imbalance between the genetic systems such as serotonin, dopamine, brain-derived neurotrophic factor, estrogen and their interactions are significantly observed in anorexic as well as recovered anorexic individuals. The dopaminergic pathway is involved in reward mechanisms but its dysfunction might cause weight loss, food aversion, hyperactivity, obsessive compulsive behaviours, distorted body image. An abnormal serotonin function reveals personality traits such as rigidity, inhibition, anxiety, inflexibility, perfectionism and harm avoidance. The Met66 variant of brain derived neurotrophic factor is strongly associated with the development of restricting-type anorexia nervosa. The development of anorexia has been linked to estrogen receptor beta gene variants, which also regulate food intake and states of anxiety and depression.This review discusses the neurobiological dysregulations because of which anorexics tend to have a distinct personality profile characterized by behaviour patterns comprising perfectionism, obsessive-compulsive disorder, harm avoidance, alexithymia, anger suppression, anxiety, rigidity, novelty seeking, anhedonia, depression, impulsivity, substance abuse, self harm etc. Heterogeneities in the characteristic profile are observed based on the subdivisions of anorexia nervosa. The impact of malnutrition has also been scrutinized.

Key role for hypothalamic interleukin-6 in food-motivated behavior and body weight regulation

The pro-inflammatory role of interleukin-6 (IL-6) is well-characterized. Blockade of IL-6, by Tocilizumab, is used in patients with rheumatoid arthritis and those diagnosed with cytokine storm. However, brain-produced IL-6 has recently emerged as a critical mediator of gut/adipose communication with the brain. Central nervous system (CNS) IL-6 is engaged by peripheral and central signals regulating energy homeostasis. IL-6 is critical for mediating hypophagia and weight loss effects of a GLP-1 analog, exendin-4, a clinically utilized drug. However, neuroanatomical substrates and behavioral mechanisms of brain IL-6 energy balance control remain poorly understood. We propose that the lateral hypothalamus (LH) is an IL-6-harboring brain region, key to food intake and food reward control. Microinjections of IL-6 into the LH reduced chow and palatable food intake in male rats. In contrast, female rats responded with reduced motivated behavior for sucrose, measured by the progressive ratio operant conditioning test, a behavioral mechanism previously not linked to IL-6. To test whether IL-6, produced in the LH, is necessary for ingestive and motivated behaviors, and body weight homeostasis, virogenetic knockdown by infusion of AAV-siRNA-IL6 into the LH was utilized. Attenuation of LH IL-6 resulted in a potent increase in sucrose-motivated behavior, without any effect on ingestive behavior or body weight in female rats. In contrast, the treatment did not affect any parameters measured (chow intake, sucrose-motivated behavior, locomotion, and body weight) in chow-fed males. However, when challenged with a high-fat/high-sugar diet, the male LH IL-6 knockdown rats displayed rapid weight gain and hyperphagia. Together, our data suggest that LH-produced IL-6 is necessary and sufficient for ingestive behavior and weight homeostasis in male rats. In females, IL-6 in the LH plays a critical role in food-motivated, but not ingestive behavior control or weight regulation. Thus, collectively these data support the idea that brain-produced IL-6 engages the hypothalamus to control feeding behavior.

Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.

The central melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are key regulators of body weight and energy homeostasis. Herein, the discovery and characterization of first-in-class small molecule melanocortin agonists with selectivity for the melanocortin-3 receptor over the melanocortin-4 receptor are reported. Identified via "unbiased" mixture-based high-throughput screening approaches, pharmacological evaluation of these pyrrolidine bis-cyclic guanidines resulted in nanomolar agonist activity at the melanocortin-3 receptor. The pharmacological profiles at the remaining melanocortin receptor subtypes tested indicated similar agonist potencies at both the melanocortin-1 and melanocortin-5 receptors and antagonist or micromolar agonist activities at the melanocortin-4 receptor. This group of small molecules represents a new area of chemical space for the melanocortin receptors with mixed receptor pharmacology profiles that may serve as novel lead compounds to modulate states of dysregulated energy balance.

STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons.

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH in energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure, or glucose homeostasis in animals on regular chow. However, with high-fat diet (HFD) challenge, loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake, and energy efficiency that was more remarkable in females, which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role in protection against DIO in a sex-specific pattern.

Basal Forebrain Cholinergic Signaling to Projection-Defined Cells within the Basolateral Amygdala Regulates Food Intake

Body weight homeostasis is regulated by balancing energy expenditure with caloric intake. Obesity, a major public health concern, often results via excess of unused caloric energy associated with overeating. The hypothalamus, which is considered the master regulator of energy homeostasis, has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extra-hypothalamic circuits throughout the brain perceive, anticipate, and adapt to food availability. We recently discovered a population of basal forebrain cholinergic neurons that regulate appetite suppression. Through viral tracing methods, we found that basal forebrain cholinergic neurons densely innervate the basolateral amygdala (BLA). The BLA has known connections to the hypothalamus and reward centers, and is implicated in appetitive behavior. However, the impact of basal forebrain cholinergic signaling on BLA-driven feeding behaviors remains largely unknown. Here, using Channelrhodopsin-assisted circuit mapping we identified muscarinic and nicotinic responses in BLA excitatory principal neurons following cholinergic basal forebrain circuit manipulations, and that BLA neurons connect to the nucleus accumbens via differential muscarinic or nicotinic circuitry. Finally, through in vivo optogenetic manipulations we show that increased cholinergic signaling from the basal forebrain to the BLA results in reduced feeding, with no major effects on stress and/or anxiety. Together these data support a model in which cholinergic signaling from the basal forebrain onto projection-defined neurons within the basolateral amygdala leads to appetite suppression.