Time-Restricted Feeding Ameliorates Methionine-Choline Deficient Diet-Induced Steatohepatitis in Mice.

Non-alcoholic steatohepatitis (NASH) is an inflammatory form of non-alcoholic fatty liver disease (NAFLD), closely associated with disease progression, cirrhosis, liver failure, and hepatocellular carcinoma. Time-restricted feeding (TRF) has been shown to decrease body weight and adiposity and improve metabolic outcomes; however, the effect of TRF on NASH has not yet been fully understood. We had previously reported that inositol polyphosphate multikinase (IPMK) mediates hepatic insulin signaling. Importantly, we have found that TRF increases hepatic IPMK levels. Therefore, we investigated whether there is a causal link between TRF and IPMK in a mouse model of NASH, i.e., methionine- and choline-deficient diet (MCDD)-induced steatohepatitis. Here, we show that TRF alleviated markers of NASH, i.e., reduced hepatic steatosis, liver triglycerides (TG), serum alanine transaminase (ALT) and aspartate aminotransferase (AST), inflammation, and fibrosis in MCDD mice. Interestingly, MCDD led to a significant reduction in IPMK levels, and the deletion of hepatic IPMK exacerbates the NASH phenotype induced by MCDD, accompanied by increased gene expression of pro-inflammatory chemokines. Conversely, TRF restored IPMK levels and significantly reduced gene expression of proinflammatory cytokines and chemokines. Our results demonstrate that TRF attenuates MCDD-induced NASH via IPMK-mediated changes in hepatic steatosis and inflammation.

Time-restricted feeding ameliorates MCDD-induced steatohepatitis in mice.

Non-Alcoholic Steatohepatitis (NASH) is an inflammatory form of Non-Alcoholic Fatty Liver Disease (NAFLD), closely associated with disease progression, cirrhosis, liver failure, and hepatocellular carcinoma. Time-restricted feeding (TRF) has been shown to decrease body weight and adiposity and improve metabolic outcomes, however, the effect of TRF on NASH has not yet been fully understood. We had previously reported that inositol polyphosphate multikinase (IPMK) mediates hepatic insulin signaling. Importantly, we have found that TRF increases hepatic IPMK levels. Therefore, we investigated whether there is a causal link between TRF and IPMK in a mouse model of NASH, i.e., methionine and choline deficient diet (MCDD)-induced steatohepatitis. Here, we show that TRF alleviated markers of NASH, i.e., reduced hepatic steatosis, liver triglycerides (TG), serum alanine transaminase (ALT) and aspartate aminotransferase (AST), inflammation and fibrosis in MCDD mice. Interestingly, MCDD led to a significant reduction in IPMK levels, and the deletion of hepatic IPMK exacerbates the NASH phenotype induced by MCDD, accompanied by increased gene expression of pro-inflammatory chemokines. Conversely, TRF restored IPMK levels and significantly reduced gene expression of proinflammatory cytokines and chemokines. Our results demonstrate that TRF attenuates MCDD-induced NASH via IPMK-mediated changes in hepatic steatosis and inflammation.

Inositol polyphosphate multikinase modulates free fatty acids-induced insulin resistance in primary mouse hepatocytes.

Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of protein kinase B (Akt) phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-acetyl cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.

Endocrine disorders associated with obesity.

Several endocrine disorders, including diabetes, insulinoma, Cushing syndrome, hypothyroidism, polycystic ovarian syndrome, and growth hormone deficiency, are associated with obesity. The mechanisms underlying the development of obesity vary according to the abnormalities of endocrine function. The primary actions of insulin, glucocorticoids (GCs), thyroid hormone, and growth hormone are associated with energy metabolism in the liver, muscle, adipose tissue, and other tissues. This chapter describes the pathogenesis of obesity and metabolic dysfunction associated with excess insulin or GCs and the deficiency of thyroid hormone or growth hormone.

IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes.

Insulin resistance is a critical mediator of the development of non-alcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of non-alcoholic fatty liver disease (NAFLD). Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of Akt phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-Acetyl Cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.

Artificial intelligence and body composition.

AIMS: Although obesity is associated with chronic disease, a large section of the population with high BMI does not have an increased risk of metabolic disease. Increased visceral adiposity and sarcopenia are also risk factors for metabolic disease in people with normal BMI. Artificial Intelligence (AI) techniques can help assess and analyze body composition parameters for predicting cardiometabolic health. The purpose of the study was to systematically explore literature involving AI techniques for body composition assessment and observe general trends. METHODS: We searched the following databases: Embase, Web of Science, and PubMed. There was a total of 354 search results. After removing duplicates, irrelevant studies, and reviews(a total of 303), 51 studies were included in the systematic review. RESULTS: AI techniques have been studied for body composition analysis in the context of diabetes mellitus, hypertension, cancer and many specialized diseases. Imaging techniques employed for AI methods include CT (Computerized Tomography), MRI (Magnetic Resonance Imaging), ultrasonography, plethysmography, and EKG(Electrocardiogram). Automatic segmentation of body composition by deep learning with convolutional networks has helped determine and quantify muscle mass. Limitations include heterogeneity of study populations, inherent bias in sampling, and lack of generalizability. Different bias mitigation strategies should be evaluated to address these problems and improve the applicability of AI to body composition analysis. CONCLUSIONS: AI assisted measurement of body composition might assist in improved cardiovascular risk stratification when applied in the appropriate clinical context.

Obesity and metabolic dysfunction correlate with background parenchymal enhancement in premenopausal women.

OBJECTIVE: This study tested the hypothesis that obesity and metabolic abnormalities correlate with background parenchymal enhancement (BPE), the volume and intensity of enhancing fibroglandular breast tissue on dynamic contrast-enhanced magnetic resonance imaging. METHODS: Participants included 59 premenopausal women at high risk of breast cancer. Obesity was defined as BMI ≥ 30 kg/m2 . Metabolic parameters included dual-energy x-ray absorptiometry-quantified body composition, plasma biomarkers of insulin resistance, adipokines, inflammation, lipids, and urinary sex hormones. BPE was assessed using computerized algorithms on dynamic contrast-enhanced magnetic resonance imaging. RESULTS: BMI was positively correlated with BPE (r = 0.69; p < 0.001); participants with obesity had higher BPE than those without obesity (404.9 ± 189.6 vs. 261.8 ± 143.8 cm2 ; Δ: 143.1 cm2 [95% CI: 49.5-236.7]; p = 0.003). Total body fat mass (r = 0.68; p < 0.001), body fat percentage (r = 0.64; p < 0.001), visceral adipose tissue area (r = 0.65; p < 0.001), subcutaneous adipose tissue area (r = 0.60; p < 0.001), insulin (r = 0.59; p < 0.001), glucose (r = 0.35; p = 0.011), homeostatic model of insulin resistance (r = 0.62; p < 0.001), and leptin (r = 0.60; p < 0.001) were positively correlated with BPE. Adiponectin (r = -0.44; p < 0.001) was negatively correlated with BPE. Plasma biomarkers of inflammation and lipids and urinary sex hormones were not correlated with BPE. CONCLUSIONS: In premenopausal women at high risk of breast cancer, increased BPE is associated with obesity, insulin resistance, leptin, and adiponectin.

IPMK modulates hepatic glucose production and insulin signaling.

Hepatic glucose production (HGP) is crucial for the maintenance of normal glucose homeostasis. Although hepatic insulin resistance contributes to excessive glucose production, its mechanism is not well understood. Here, we show that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo. IPMK-deficient hepatocytes exhibit decreased insulin-induced activation of Akt-FoxO1 signaling. The expression of messenger RNA levels of phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose 6-phosphatase (G6pc), key enzymes mediating gluconeogenesis, are increased in IPMK-deficient hepatocytes compared to wild type hepatocytes. Importantly, re-expressing IPMK restores insulin sensitivity and alleviates glucose production in IPMK-deficient hepatocytes. Moreover, hepatocyte-specific IPMK deletion exacerbates hyperglycemia and insulin sensitivity in mice fed a high-fat diet, accompanied by an increase in HGP during pyruvate tolerance test and reduction in Akt phosphorylation in IPMK deficient liver. Our results demonstrate that IPMK mediates insulin signaling and gluconeogenesis and may be potentially targeted for treatment of diabetes.

Correlates of cardiorespiratory fitness among overweight or obese individuals with type 2 diabetes.

INTRODUCTION: Mechanistic studies suggest that type 2 diabetes is independently associated with low cardiorespiratory fitness (CRF). Little is known about the CRF profile in type 2 diabetes; we assessed the correlates of low CRF among overweight/obese adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 4215 participants with type 2 diabetes and without cardiovascular disease underwent maximal exercise testing in the Look AHEAD (Action for Health in Diabetes) study. Low CRF was defined based on the Aerobics Center Longitudinal Study reference standards. Calorie intake and physical activity were assessed using questionnaires. Body fat composition was assessed using dual-energy X-ray absorptiometry. RESULTS: Waist circumference, systolic blood pressure, glycemic measures, whole body fat, caloric intake, and fat-free mass were inversely associated with fitness across sex (all p<0.001). Comparing with moderate or high CRF groups, the low CRF group was associated with higher adjusted odds of obesity (OR 3.19 (95% CI 1.95 to 5.20) in men, 3.86 (95% CI 2.55 to 5.84)) in women), abdominal obesity (OR 3.99 (95% CI 2.00 to 7.96) in men, 2.28 (95% CI 1.08 to 4.79) in women), hypertension (OR 1.74 (95% CI 1.09 to 2.77) in men, 1.44 (95% CI 1.02 to 2.05) in women), metabolic syndrome (OR 5.52 (95% CI 2.51 to 12.14) in men, 2.25 (95% CI 1.35 to 3.76) in women), use of beta-blocker (1.22 (95% CI 0.86 to 1.73) in men, 1.33 (95% CI 1.03 to 1.73) in women), and ACE inhibitor/angiotensin-receptor blocker (1.86 (95% CI 1.39 to 2.50) in men, 1.07 (95% CI 0.86 to 1.32) in women). Women with low CRF had higher odds of current smoking (2.02 (95% CI 1.25 to 3.28)). CONCLUSIONS: Low CRF was associated with increased odds of cardiometabolic correlates in a large cohort of adults with type 2 diabetes.

A systematic review of imaging studies of human brown adipose tissue.

Brown adipose tissue (BAT) is involved in energy dissipation and has been linked to weight loss, insulin sensitivity, and reduced risk of atherosclerotic disease. BAT is found most often in the supraclavicular region, as well as mediastinal and paravertebral areas, and it is predominantly seen in young persons. BAT is activated by cold temperature and the sympathetic nervous system. In humans, BAT was initially detected via 2-deoxy-2-[18 F]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT), a high-resolution molecular imaging modality used to identify and stage malignancies. Recent studies have shown that BAT can be localized using conventional imaging modalities, such as CT or magnetic resonance imaging, as well as radiotracers used for single-photon emission CT. In this systematic review, we have summarized the evidence for BAT detection in humans using various imaging techniques.

Preoperative BMI Predicts Postoperative Weight Gain in Adult-onset Craniopharyngioma.

CONTEXT: Craniopharyngiomas, while benign, have the highest morbidity of all nonmalignant sellar tumors. Studies on weight and metabolic outcomes in adult-onset craniopharyngioma (AOCP) remain sparse. OBJECTIVE: To examine postsurgical weight and metabolic outcomes in AOCP and to identify any clinical predictors of weight gain. METHODS: Retrospective chart review of patients with AOCP who underwent surgery between January 2014 and May 2019 in a single pituitary center. The study included 45 patients with AOCP with a minimum follow-up of 3 months. Median follow-up time was 26 months (interquartile range [IQR] 10-44). Main outcome measures were the changes in weight/body mass index (BMI), metabolic comorbidities, and pituitary deficiencies between preoperative and last follow-up. RESULTS: Both weight and BMI were higher at last follow-up, with a mean increase of 3.4 kg for weight (P = .015) and 1.15 kg/m2 for BMI (P = .0095). Median % weight change was 2.7% (IQR -1.1%, 8.8%). Obesity rate increased from 37.8% at baseline to 55.6% at last follow-up. One-third of patients had ~15% median weight gain. The prevalence of metabolic comorbidities at last follow-up was not different from baseline. Pituitary deficiencies increased postoperatively, with 58% of patients having ≥3 hormonal deficiencies. Preoperative BMI was inversely associated with postoperative weight gain, which remained significant after adjusting for age, sex, race, tumor, and treatment characteristics. Patients with ≥3 hormonal deficiencies at last follow-up also had higher postoperative weight gain. CONCLUSION: In this AOCP cohort, those with a lower BMI at the preoperative visit had higher postoperative weight gain. Our finding may help physicians better counsel patients and provide anticipatory guidance on postoperative expectations and management.

Discrimination Is Associated with Elevated Cardiovascular Disease Risk among African Immigrants in the African Immigrant Health Study.

Background: African Americans and other persons of African descent in the United States are disproportionately affected by cardiovascular diseases (CVD). Discrimination is associated with higher CVD risk among US adults; however, this relationship is unknown among African immigrants. Methods: The African Immigrant Health Study was a cross-sectional study of African immigrants in Baltimore-Washington, DC, with recruitment and data collection taking place between June 2017 and April 2019. The main outcome was elevated CVD risk, the presence of ≥3 CVD risk factors including hypertension, diabetes, high cholesterol, overweight/obesity, tobacco use, and poor diet. The secondary outcomes were these six individual CVD risk factors. The exposure was discrimination measured with the Everyday Discrimination Scale; summed scores ≥2 on each item indicated frequent experiences of discrimination. Resilience was assessed with the 10-item Connor-Davidson resilience scale. Logistic regression was used to examine the odds of elevated CVD risk, adjusting for relevant covariates. Results: We included 342 participants; 61% were females. The mean (±SD) age was 47(±11) years, 61% had at least a bachelor's degree, 18% had an income <$40,000, and 49% had lived in the US ≥15 years. Persons with frequent experiences of discrimination were 1.82 times (95%CI: 1.04-3.21) more likely to have elevated CVD risk than those with fewer experiences. Resilience did not moderate the relationship between CVD risk and discrimination. Conclusion: African immigrants with frequent experiences of discrimination were more likely to have elevated CVD risk. Targeted and culturally appropriate interventions are needed to reduce the high burden of CVD risk in this population. Health care providers should be aware of discrimination as a meaningful social determinant of CVD risk. At the societal level, policies and laws are needed to reduce the occurrence of discrimination among African immigrants and racial/ethnic minorities.

Lipid accumulation and oxidation in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor in adults. Despite the multimodal standard treatments for GBM, the median survival is still about one year. Analysis of brain tissues from GBM patients shows that lipid droplets are highly enriched in tumor tissues while undetectable in normal brain tissues, yet the identity and functions of lipid species in GBM are not well understood. The aims of the present work are to determine how GBM utilizes fatty acids, and assess their roles in GBM proliferation. Treatment of U138 GBM cells with a monounsaturated fatty acid, oleic acid, induces accumulation of perilipin 2-coated lipid droplets containing triglycerides enriched in C18:1 fatty acid, and increases fatty acid oxidation. Interestingly, oleic acid also increases glucose utilization and proliferation of GBM cells. In contrast, pharmacologic inhibition of monoacylglycerol lipase attenuates GBM proliferation. Our findings demonstrate that monounsaturated fatty acids promote GBM proliferation via triglyceride metabolism, suggesting a novel lipid droplet-mediated pathway which may be targeted for GBM treatment.

Insulin and adipokine signaling and their cross-regulation in postmortem human brain.

Aberrant insulin and adipokine signaling has been implicated in cognitive decline associated with both type 2 diabetes mellitus and neurodegenerative diseases. We established methods that reliably measure insulin, adiponectin and leptin signaling, and their crosstalk, in thawed postmortem mid-frontal cortical tissue from cognitively normal older subjects with a short postmortem interval. Insulin-evoked insulin receptor (IR) activation increases activated, tyrosine-phosphorylated IRß on tyrosine residues 960, 1150, and 1151, insulin receptor substrate-1 recruitment to IRß and phosphorylated RAC-α-serine/threonine-protein kinase. Adiponectin augments, but leptin inhibits, insulin signaling. Adiponectin activates adiponectin receptors to induce APPL1 binding to adiponectin receptor 1 and 2 and T-cadherin and downstream adenosine monophosphate-dependent protein kinase phosphorylation. Insulin inhibited adiponectin-induced signaling. In addition, leptin-induced leptin receptor (OB-R) signaling promotes Janus kinase 2 recruitment to OB-R and Janus kinase 2 and downstream signal transducer and activator of transcription 3 phosphorylation. Insulin enhanced leptin signaling. These data demonstrate insulin and adipokine signaling interactions in human brain. Future studies can use these methods to examine insulin, adiponectin, and leptin metabolic dysregulation in aging and disease states, such as type 2 diabetes and Alzheimer's disease-related dementias.

Differential Effects of Roux-en-Y Gastric Bypass Surgery and Laparoscopic Sleeve Gastrectomy on Fatty Acid Levels.

BACKGROUND: Bariatric surgery is associated with improved cardiovascular outcomes and also affects lipid levels, but few studies have compared the effects of Roux-en-Y gastric bypass (RYGB) surgery with those of laparoscopic sleeve gastrectomy (LSG) on serum fatty acid levels. The present study compares the effects of RYGB and LSG surgeries on serum fatty acid levels. METHODS: The study participants were women who were undergoing either RYGB or LSG and body mass index (BMI)-matched controls. Fasting blood samples to measure glucose, insulin, and fatty acids were drawn at baseline and at 6 and 18 months from baseline. RESULTS: Serum fatty acid data were available for 57 participants at baseline, of whom 56 had data at 6 months and 41 had data at 18 months from baseline. Compared with baseline, serum non-esterified fatty acids (NEFAs) levels were significantly higher at 6 and 18 months in the LSG group compared with the RYGB group. In the RYGB group, 2 saturated fatty acids (SFAs), 2 monounsaturated fatty acids (MUFAs), and 1 polyunsaturated fatty acid (PUFA) were significantly decreased after surgery, compared with those of the LSG group. CONCLUSIONS: A significant increase in NEFAs was seen after LSG, compared with RYGB. Compared with the LSG group, several serum fatty acids were significantly reduced after RYGB. TRIAL REGISTRATION: NCT01228097.

Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation.

Mitochondrial Ca2+ uniporter (MCU)-mediated Ca2+ uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCUΔhep) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca2+ (mCa2+) uptake, delays cytosolic Ca2+ (cCa2+) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhep were a direct result of extramitochondrial Ca2+-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhep hepatocytes. Conversely, gain-of-function MCU promotes rapid mCa2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+ dynamics to hepatic lipid metabolism.

Modulation of Glucose Metabolism in Hippocampal Neurons by Adiponectin and Resistin.

Obese individuals exhibit altered circulating levels of adipokines, the proteins secreted by adipose tissue to mediate tissue cross-talk and regulate appetite and energy expenditure. The effect of adipokines on neuronal glucose metabolism, however, remains largely unknown. Two adipokines produced in adipose tissue, adiponectin and resistin, can gain access to the central nervous system (CNS), and their levels in the cerebrospinal fluid (CSF) are altered in obesity. We hypothesized that dysregulated adipokines in the CNS may underlie the reported link between obesity and higher risk of neurological disorders like Alzheimer's disease (AD), by affecting glucose metabolism in hippocampal neurons. Using cultured primary rat hippocampal neurons and mouse hippocampus slices, we show that recombinant adiponectin and resistin, at a concentration found in the CSF, have opposing effects on glucose metabolism. Adiponectin enhanced glucose uptake, glycolytic rate, and ATP production through an AMP-activated protein kinase (AMPK)-dependent mechanism; inhibiting AMPK abrogated the effects of adiponectin on glucose uptake and utilization. In contrast, resistin reduced glucose uptake, glycolytic rate, and ATP production, in part, by inhibiting hexokinase (HK) activity in hippocampal neurons. These data suggest that altered CNS levels of adipokines in the context of obesity may impact glucose metabolism in hippocampal neurons, brain region involved in learning and memory functions.

Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture.

OBJECTIVE: Adult obesity risk is influenced by alterations to fetal and neonatal environments. Modifying neonatal gut or neurohormone signaling pathways can have negative metabolic consequences in adulthood. Here we characterize the effect of neonatal activation of glucagon like peptide-1 (GLP-1) receptor (GLP1R) signaling on adult adiposity and metabolism. METHODS: Wild type C57BL/6 mice were injected with 1 nmol/kg Exendin-4 (Ex-4), a GLP1R agonist, for 6 consecutive days after birth. Growth, body composition, serum analysis, energy expenditure, food intake, and brain and fat pad histology and gene expression were assessed at multiple time points through 42 weeks. Similar analyses were conducted in a Glp1r conditional allele crossed with a Sim1Cre deleter strain to produce Sim1Cre;Glp1rloxP/loxP mice and control littermates. RESULTS: Neonatal administration of Ex-4 reduced adult body weight and fat mass, increased energy expenditure, and conferred protection from diet-induced obesity in female mice. This was associated with induction of brown adipose genes and increased noradrenergic fiber density in parametrial white adipose tissue (WAT). We further observed durable alterations in orexigenic and anorexigenic projections to the paraventricular hypothalamic nucleus (PVH). Genetic deletion of Glp1r in the PVH by Sim1-Cre abrogated the impact of neonatal Ex-4 on adult body weight, WAT browning, and hypothalamic architecture. CONCLUSION: These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.