ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.

Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR) by nutrient excess.

Cardiac NAD depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.

Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD levels, and supplementation with NAD precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity.

Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming.

The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process in mice. We found that aging increases the expression of and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes.

Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism.

Objective: Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight loss is fat mass, there is also a loss of lean mass, similar to other approaches that induce calorie deficit. Targeting signaling pathways that regulate skeletal muscle hypertrophy is a promising avenue to preserve lean mass and modulate body composition.

Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming.

The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process. We found that aging increases the expression of and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes.

Inducible hepatic expression of CREBH mitigates diet-induced obesity, insulin resistance, and hepatic steatosis in mice.

Cyclic AMP-responsive element-binding protein H (CREBH encoded by Creb3l3) is a transcription factor that regulates the expression of genes that control lipid and glucose metabolism as well as inflammation. CREBH is upregulated in the liver under conditions of overnutrition, and mice globally lacking the gene (CREBH) are highly susceptible to diet-induced obesity, insulin resistance, and hepatic steatosis. The net protective effects of CREBH have been attributed in large part to the activities of fibroblast growth factor (Fgf)-21 (Fgf21), a target gene that promotes weight loss, improves glucose homeostasis, and reduces hepatic lipid accumulation.

Defining the lineage of thermogenic perivascular adipose tissue.

Brown adipose tissue can expend large amounts of energy, and therefore increasing its size or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood.

Acyl-Coenzyme A Thioesterase 9 Traffics Mitochondrial Short-Chain Fatty Acids Toward De Novo Lipogenesis and Glucose Production in the Liver.

Background And Aims: Obesity-induced pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is associated with increased de novo lipogenesis (DNL) and hepatic glucose production (HGP) that is due to excess fatty acids. Acyl-coenzyme A (CoA) thioesterase (Acot) family members control the cellular utilization of fatty acids by hydrolyzing (deactivating) acyl-CoA into nonesterified fatty acids and CoASH.

Approach And Results: Using Caenorhabditis elegans, we identified Acot9 as the strongest regulator of lipid accumulation within the Acot family.

Dissociation of Adaptive Thermogenesis from Glucose Homeostasis in Microbiome-Deficient Mice.

Recent studies suggest that a key mechanism whereby the gut microbiome influences energy balance and glucose homeostasis is through the recruitment of brown and beige adipocytes, primary mediators of the adaptive thermogenic response. To test this, we assessed energy expenditure and glucose metabolism in two complementary mouse models of gut microbial deficiency, which were exposed to a broad range of thermal and dietary stresses. Neither ablation of the gut microbiome, nor the substantial microbial perturbations induced by cold ambient temperatures, influenced energy expenditure during cold exposure or high-fat feeding.

Knockout of the X-linked in the hypothalamic paraventricular nucleus impairs sympathetic output to brown fat and causes obesity.

Fibroblast growth factor (FGF)13, a nonsecreted, X-linked, FGF homologous factor, is differentially expressed in adipocytes in response to diet, yet 's role in metabolism has not been explored. Heterozygous knockouts fed normal chow and housed at 22°C showed hyperactivity accompanying reduced core temperature and obesity when housed at 30°C. Those heterozygous knockouts showed defects in thermogenesis even at 30°C and an inability to protect core temperature.

Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice.

Bone marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. Recent studies indicate that the intestinal microbiota not only regulates mucosal immunity, but can also contribute to systemic immunity and hematopoiesis. Using antibiotic-mediated microbiota depletion in a syngeneic BMT mouse model, here we describe a role for the intestinal flora in hematopoietic recovery after BMT.