AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation.

During postnatal life, leptin specifies neuronal inputs to the paraventricular nucleus of the hypothalamus (PVH) and activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms impact refinement of sensory circuits, but whether leptin-mediated postnatal neuronal activity specifies hypothalamic neural projections is largely unexplored. Here, we used chemogenetics to manipulate the activity of AgRP neurons during a discrete postnatal critical period and evaluated the development of AgRP inputs to the PVH and descending efferent outflow to the dorsal vagal complex (DVC).

Validation of a refined protocol for mouse oral glucose tolerance testing without gavage.

A glucose tolerance test (GTT) is routinely used to assess glucose homeostasis in clinical settings and in preclinical research studies using rodent models. The procedure assesses the ability of the body to clear glucose from the blood in a defined time after a bolus dose. In the human clinical setting, glucose is ingested via voluntary consumption of a glucose-sweetened drink.

The mouse metabolic phenotyping center (MMPC) live consortium: an NIH resource for in vivo characterization of mouse models of diabetes and obesity.

The Mouse Metabolic Phenotyping Center (MMPC)Live Program was established in 2023 by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high quality phenotyping services for mouse models of diabetes and obesity. Emerging as the next iteration of the MMPC Program which served the biomedical research community for 20 years (2001-2021), MMPCLive is designed as an outwardly-facing consortium of service cores that collaborate to provide reduced-cost consultation and metabolic, physiologic, and behavioral phenotyping tests on live mice for U.S.

Time-dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets.

Objective: Obesity is characterized by dysregulated homeostatic mechanisms resulting in positive energy balance; however, when this dysregulation occurs is unknown. We assessed the time course of alterations to behaviors promoting weight gain in male and female mice switched to an obesogenic high-fat diet (HFD).

Methods: Male and female C57BL/6J mice were housed in metabolic chambers and were switched from chow to a 60% or 45% HFD for 4 and 3 weeks, respectively.

AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation.

Unlabelled: During postnatal life, the adipocyte-derived hormone leptin is required for proper targeting of neural inputs to the paraventricular nucleus of the hypothalamus (PVH) and impacts the activity of neurons containing agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms are known to play a defining role during postnatal organization of neural circuits, but whether leptin-mediated postnatal neuronal activity specifies neural projections to the PVH or impacts downstream connectivity is largely unexplored. Here, we blocked neuronal activity of AgRP neurons during a discrete postnatal period and evaluated development of AgRP inputs to defined regions in the PVH, as well as descending projections from PVH oxytocin neurons to the dorsal vagal complex (DVC) and assessed their dependence on leptin or postnatal AgRP neuronal activity.

Time dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets.

Unlabelled: Obesity is characterized by dysregulated homeostatic mechanisms resulting in positive energy balance, yet when this dysregulation occurs is unknown. We assessed the time course of alterations to behaviors promoting weight gain in male and female mice switched to obesogenic 60% or 45% high fat diet (HFD). Switching mice to obesogenic diets promotes transient bouts of hyperphagia during the first 2 weeks followed by persistent caloric hyperphagia.

Glucagon-like peptide-1 receptor activation stimulates PKA-mediated phosphorylation of Raptor and this contributes to the weight loss effect of liraglutide.

The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide. We measured phosphorylation of the mTORC1 signaling target ribosomal protein S6 in Chinese Hamster Ovary cells expressing GLP-1R (CHO-Glp1r) treated with liraglutide in combination with PKA inhibitors.

Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity.

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from Gi/o GPCRs by Gβγ subunit inhibition of 2 mechanisms: decreased calcium entry and direct interaction of Gβγ with soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) plasma membrane fusion machinery. Previously, we disabled the second mechanism with a SNAP25 truncation (SNAP25Δ3) that decreased Gβγ affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact and removing GPCR-Gβγ inhibition of SNARE-mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation.

Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets.

Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RA) and fibroblast growth factor-21 (FGF21) confer similar metabolic benefits. GLP-1RA induce FGF21, leading us to investigate mechanisms engaged by the GLP-1RA liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21.

Methods: Circulating FGF21 levels were measured in fasted male C57BL/6J, neuronal GLP-1R knockout, β-cell GLP-1R knockout, and liver peroxisome proliferator-activated receptor alpha knockout mice treated acutely with liraglutide.

The TAS1R2 sweet taste receptor regulates skeletal muscle mass and fitness.

Muscle fitness and mass deteriorate under the conditions of obesity and aging for reasons yet to be fully elucidated. Herein, we describe a novel pathway linking peripheral nutrient sensing and skeletal muscle function through the sweet taste receptor TAS1R2 and the involvement of ERK2-PARP1-NAD signaling axis. Muscle-specific deletion of TAS1R2 (mKO) in mice produced elevated NAD levels due to suppressed PARP1 activity, improved mitochondrial function, increased muscle mass and strength, and prolonged running endurance.

Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide in Male Mice fed High Carbohydrate Diets.

Glucagon-like peptide-1 receptor (GLP-1R) agonists and fibroblast growth factor 21 (FGF21) confer similar metabolic benefits. Studies report that GLP-1RA induce FGF21. Here, we investigated the mechanisms engaged by the GLP-1R agonist liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21.

Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis.

Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety.

High fat diet blunts stress-induced hypophagia and activation of Glp1r dorsal lateral septum neurons in male but not in female mice.

Objective: While stress typically reduces caloric intake (hypophagia) in chow-fed rodents, presentation of palatable, high calorie substances during stress can increase caloric consumption (i.e. "comfort feeding") and promote obesity.

IL18 signaling causes islet β cell development and insulin secretion via different receptors on acinar and β cells.

Diabetic patients show elevated plasma IL18 concentrations. IL18 has two receptors: the IL18 receptor (IL18r) and the Na-Cl co-transporter (NCC). Here, we report that IL18 is expressed on islet α cells, NCC on β cells, and IL18r on acinar cells in human and mouse pancreases.

/ depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice.

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin may contribute to fatty liver disease.

Mannose Alters Gut Microbiome, Prevents Diet-Induced Obesity, and Improves Host Metabolism.

Mannose is an important monosaccharide for protein glycosylation in mammals but is an inefficient cellular energy source. Using a C57BL6/J mouse model of diet-induced obesity, we show that mannose supplementation of high-fat-diet-fed mice prevents weight gain, lowers adiposity, reduces liver steatosis, increases endurance and maximal O consumption, and improves glucose tolerance. Mannose-supplemented mice have higher fecal energy content, suggesting reduced caloric absorption by the host.

Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice.

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis).

Elevated Nicotinamide Phosphoribosyl Transferase in Skeletal Muscle Augments Exercise Performance and Mitochondrial Respiratory Capacity Following Exercise Training.

Mice overexpressing NAMPT in skeletal muscle (NamptTg mice) develop higher exercise endurance and maximal aerobic capacity (VOmax) following voluntary exercise training compared to wild-type (WT) mice. Here, we aimed to investigate the mechanisms underlying by determining skeletal muscle mitochondrial respiratory capacity in NamptTg and WT mice. Body weight and body composition, tissue weight (gastrocnemius, quadriceps, soleus, heart, liver, and epididymal white adipose tissue), skeletal muscle and liver glycogen content, VOmax, skeletal muscle mitochondrial respiratory capacity (measured by high-resolution respirometry), skeletal muscle gene expression (measured by microarray and qPCR), and skeletal muscle protein content (measured by Western blot) were determined following 6 weeks of voluntary exercise training (access to running wheel) in 13-week-old male NamptTg (exercised NamptTg) mice and WT (exercised WT) mice.

Impaired Mitochondrial Energetics Characterize Poor Early Recovery of Muscle Mass Following Hind Limb Unloading in Old Mice.

The progression of age-related sarcopenia can be accelerated by impaired recovery of muscle mass following periods of disuse due to illness or immobilization. However, the mechanisms underlying poor recovery of aged muscle following disuse remain to be delineated. Recent evidence suggests that mitochondrial energetics play an important role in regulation of muscle mass.

Skeletal muscle overexpression of nicotinamide phosphoribosyl transferase in mice coupled with voluntary exercise augments exercise endurance.

Objective: Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD), an essential co-substrate regulating a myriad of signaling pathways. We produced a mouse that overexpressed NAMPT in skeletal muscle (NamptTg) and hypothesized that NamptTg mice would have increased oxidative capacity, endurance performance, and mitochondrial gene expression, and would be rescued from metabolic abnormalities that developed with high fat diet (HFD) feeding.

Methods: Insulin sensitivity (hyperinsulinemic-euglycemic clamp) was assessed in NamptTg and WT mice fed very high fat diet (VHFD, 60% by kcal) or chow diet (CD).

The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect.

Oleoylethanolamide: A fat ally in the fight against obesity.

Obesity is a pandemic, gateway disease that has thrived in modern, sedentary, high calorie-eating societies. Left unchecked, obesity and obesity-related diseases will continue to plague future generations with heavy burdens on economies, healthcare systems, and the quality of life of billions. There is a significant need to elucidate basic physiological mechanisms and therapies that address this global health care crisis.