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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α 1 -adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation., Competing Interests: Declaration of interests D.J.D. has consulted for Altimmune, Amgen, Kallyope, Merck, Novo Nordisk, Pfizer Inc., and Sanofi Inc. Mt. Sinai Hospital receives operating grant support from Amgen, Novo Nordisk, and Pfizer Inc. for studies in the Drucker lab. R.J.S. has consulted for Novo Nordisk, Scohia, CinRx, Fractyl, Structure Therapeutics, Congruenc Therapeutics, Calibrate, and Rewind and receives operating grant support from Novo Nordisk, Astra Zeneca, Fractyl, and Eli Lilly Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Glucagon-like peptide-1 (GLP-1) controls islet hormone secretion, gut motility, and body weight, supporting development of GLP-1 receptor agonists (GLP-1RA) for the treatment of type 2 diabetes (T2D) and obesity. GLP-1RA exhibit a favorable safety profile and reduce the incidence of major adverse cardiovascular events in people with T2D. Considerable preclinical data, supported by the results of clinical trials, link therapy with GLP-RA to reduction of hepatic inflammation, steatosis, and fibrosis. Mechanistically, the actions of GLP-1 on the liver are primarily indirect, as hepatocytes, Kupffer cells, and stellate cells do not express the canonical GLP-1R. GLP-1RA reduce appetite and body weight, decrease postprandial lipoprotein secretion, and attenuate systemic and tissue inflammation, actions that may contribute to attenuation of metabolic-associated fatty liver disease (MAFLD). Here we discuss evolving concepts of GLP-1 action that improve liver health and highlight evidence that links sustained GLP-1R activation in distinct cell types to control of hepatic glucose and lipid metabolism, and reduction of experimental and clinical nonalcoholic steatohepatitis (NASH). The therapeutic potential of GLP-1RA alone, or in combination with peptide agonists, or new small molecule therapeutics is discussed in the context of potential efficacy and safety. Ongoing trials in people with obesity will further clarify the safety of GLP-1RA, and pivotal studies underway in people with NASH will define whether GLP-1-based medicines represent effective and safe therapies for people with MAFLD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In rodents, lower brown adipose tissue (BAT) activity is associated with greater liver steatosis and changes in the gut microbiome. However, little is known about these relationships in humans. In adults (n = 60), we assessed hepatic fat and cold-stimulated BAT activity using magnetic resonance imaging and the gut microbiota with 16S sequencing. We transplanted gnotobiotic mice with feces from humans to assess the transferability of BAT activity through the microbiota. Individuals with NAFLD (n = 29) have lower BAT activity than those without, and BAT activity is inversely related to hepatic fat content. BAT activity is not related to the characteristics of the fecal microbiota and is not transmissible through fecal transplantation to mice. Thus, low BAT activity is associated with higher hepatic fat accumulation in human adults, but this does not appear to have been mediated through the gut microbiota., Competing Interests: B.A.A. holds the Lau Family scholarship for science and engineering and was funded by the Ontario graduate scholarship. D.P.B. holds the GlaxoSmithKline (GSK) Chair in Diabetes of Université de Sherbrooke, which was created in part through a donation of $1 million by GSK to Université de Sherbrooke. D.P.B. has received honoraria and consulting fees from Boehringer Ingelheim. S.A.S. holds a CIHR Vanier Canada Graduate Scholarship. E.M.D. holds a CIHR Vanier Canada Graduate Scholarship. F.F.A. holds a CIHR postdoctoral fellowship and Diabetes Canada incentive funding. A.C.H. holds research funding from the CIHR and the Natural Sciences and Engineering Research Council of Canada. A.C.C. holds the Canada Research Chair in Molecular Imaging of Diabetes and research funding from the CIHR, Fonds de recherche Québec – Santé, and has participated in advisory boards for Amgen, UniQure, Merck, Janssen, Novo Nordisk, Novartis, HLS Therapeutics Inc., TVM Life Science Management, AstraZeneca, and Eli Lilly and participated in one conference sponsored by AstraZeneca. M.G.S. is funded by the CIHR, Genome Canada, and the W. Garfield Weston Foundation and holds a Tier 1 Canada Research Chair in Interdisciplinary Microbiome Research. J.D.S. receives funding from the CIHR (FDN-154295) and holds a Canada Research Chair in Metabolic Inflammation. Z.P. has received honoraria for advice and speaking from Abbott, Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, and Sanofi, and has received research funds from Amgen, Astra Zeneca/Bristol Myers Squibb, Lexicon, Merck, Novo Nordisk, Sanofi, and the CIHR. G.R.S. receives funding from the CIHR (201709FDN-CEBA-116200), Diabetes Canada Investigator Award (DI-5-17-5302-GS), a Tier 1 Canada Research Chair, and the J. Bruce Duncan Endowed Chair in Metabolic Diseases. He also receives research funding from Espervita Therapeutics, Esperion Therapeutics, Novo Nordisk, and Poxel Pharma and honoraria and consulting fees from Astra Zeneca, Eli Lilly, Esperion Therapeutics, Poxel, and Merck. K.M.M. holds research funding from the CIHR, Heart and Stroke Foundation of Canada, McMaster Children’s Hospital Foundation, and McMaster University. She has received research funds from Astra Zeneca and is an advisory board member for Novo Nordisk and Akcea Therapeutics, Canada., (© 2021 The Author(s).)

Objective: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and potentially in BAT. Herein, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed whether γ3 plays a role in adipose thermogenesis and browning., Methods: Global AMPKγ3 knockout (KO) mice were generated. A systematic whole-body, tissue, and molecular phenotyping linked to glucose homeostasis was performed in γ3 KO and wild-type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo as well as blood glucose clearance in response to small molecule AMPK activators that target the nucleotide-binding domain of the γ subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the α and β subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a β3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics, and function., Results: Genetic ablation of γ3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high-fat diet. γ3 deficiency had no effect on fiber-type composition, mitochondrial content and components, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in γ3 KO mice showed a partial loss of AMPKα2 activity, which was associated with reduced levels of AMPKα2 and β2 subunit isoforms. Notably, γ3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose-lowering in vivo and glucose uptake specifically in glycolytic muscle ex vivo. We detected γ3 in BAT and found that it preferentially interacts with α2 and β2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and γ3 KO mice., Conclusions: These results demonstrate that γ3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that γ3 is dispensable for β3-adrenergic receptor agonist-induced thermogenesis and browning of iWAT., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic., (© 2021. The Author(s).)

Obesity is linked with insulin resistance and is characterized by excessive accumulation of adipose tissue due to chronic energy imbalance. Increasing thermogenic brown and beige adipose tissue futile cycling may be an important strategy to increase energy expenditure in obesity, however, brown adipose tissue metabolic activity is lower with obesity. Herein, we report that the exposure of mice to thermoneutrality promotes the infiltration of white adipose tissue with mast cells that are highly enriched with tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme regulating peripheral serotonin synthesis. Engraftment of mast cell-deficient mice with Tph1 -/- mast cells or selective mast cell deletion of Tph1 enhances uncoupling protein 1 (Ucp1) expression in white adipose tissue and protects mice from developing obesity and insulin resistance. These data suggest that therapies aimed at inhibiting mast cell Tph1 may represent a therapeutic approach for the treatment of obesity and type 2 diabetes.

The gut microbiome is an established regulator of aspects of host metabolism, such as glucose handling. Despite the known impacts of the gut microbiota on host glucose homeostasis, the underlying mechanisms are unknown. The gut microbiome is also a potent mediator of gut-derived serotonin synthesis, and this peripheral source of serotonin is itself a regulator of glucose homeostasis. Here, we determined whether the gut microbiome influences glucose homeostasis through effects on gut-derived serotonin. Using both pharmacological inhibition and genetic deletion of gut-derived serotonin synthesis, we find that the improvements in host glucose handling caused by antibiotic-induced changes in microbiota composition are dependent on the synthesis of peripheral serotonin., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Serotonin is a phylogenetically ancient biogenic amine that has played an integral role in maintaining energy homeostasis for billions of years. In mammals, serotonin produced within the central nervous system regulates behavior, suppresses appetite, and promotes energy expenditure by increasing sympathetic drive to brown adipose tissue. In addition to these central circuits, emerging evidence also suggests an important role for peripheral serotonin as a factor that enhances nutrient absorption and storage. Specifically, glucose and fatty acids stimulate the release of serotonin from the duodenum, promoting gut peristalsis and nutrient absorption. Serotonin also enters the bloodstream and interacts with multiple organs, priming the body for energy storage by promoting insulin secretion and de novo lipogenesis in the liver and white adipose tissue, while reducing lipolysis and the metabolic activity of brown and beige adipose tissue. Collectively, peripheral serotonin acts as an endocrine factor to promote the efficient storage of energy by upregulating lipid anabolism. Pharmacological inhibition of serotonin synthesis or signaling in key metabolic tissues are potential drug targets for obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD)., (Copyright © 2019 Endocrine Society.)

Objective: Fibroblast growth factor 21 (FGF21) shows great potential for the treatment of obesity and type 2 diabetes, as its long-acting analogue reduces body weight and improves lipid profiles of participants in clinical studies; however, the intracellular mechanisms mediating these effects are poorly understood. AMP-activated protein kinase (AMPK) is an important energy sensor of the cell and a molecular target for anti-diabetic medications. This work examined the role of AMPK in mediating the glucose and lipid-lowering effects of FGF21., Methods: Inducible adipocyte AMPK β1β2 knockout mice (iβ1β2AKO) and littermate controls were fed a high fat diet (HFD) and treated with native FGF21 or saline for two weeks. Additionally, HFD-fed mice with knock-in mutations on the AMPK phosphorylation sites of acetyl-CoA carboxylase (ACC)1 and ACC2 (DKI mice) along with wild-type (WT) controls received long-acting FGF21 for two weeks., Results: Consistent with previous studies, FGF21 treatment significantly reduced body weight, adiposity, and liver lipids in HFD fed mice. To add, FGF21 improved circulating lipids, glycemic control, and insulin sensitivity. These effects were independent of adipocyte AMPK and were not associated with changes in browning of white (WAT) and brown adipose tissue (BAT). Lastly, we assessed whether FGF21 exerted its effects through the AMPK/ACC axis, which is critical in the therapeutic benefits of the anti-diabetic medication metformin. ACC DKI mice had improved glucose and insulin tolerance and a reduction in body weight, body fat and hepatic steatosis similar to WT mice in response to FGF21 administration., Conclusions: These data illustrate that the metabolic improvements upon FGF21 administration are independent of adipocyte AMPK, and do not require the inhibitory action of AMPK on ACC. This is in contrast to the anti-diabetic medication metformin and suggests that the treatment of obesity and diabetes with the combination of FGF21 and AMPK activators merits consideration.

Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.