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It has been a long-held belief that the hormone ghrelin is activated when an animal is hungry, inducing the brain to increase food intake. Now, Matthias Tschöp and his colleagues show in vivo that it is not the deficiency of calories per se that activates ghrelin, but rather the presence of energy-rich medium-chain dietary fats.

A new study shows that withaferin A, a steroidal lactone isolated from Withania somnifera, can exert profound metabolic benefits in mice, including body-weight loss, reduced hepatic steatosis and improved glucose control.

Over the past decade, the field of metabolism has witnessed remarkable scientific discoveries that reshaped the understanding of metabolic physiology and disease. As we launch Nature Metabolism, we look at what the future holds for metabolic research.

Endothermy facilitated mammalian species radiation, but the events leading to sustained thermogenesis are not clear. Here, the authors report functional brown adipose tissue in a protoendothermic mammal, linking nonshivering thermogenesis directly to the roots of eutherian endothermic evolution.

Estrogen is beneficial for obesity and type 2 diabetes, though its use is limited by important side effects. In a new study, Matthias Tschöp and colleagues avoid this issue by chemically linking estrogen to the hormone GLP-1 to selectively target metabolically relevant tissue and show that the conjugated compound corrects obesity, hyperglycemia and dyslipidemia in mice. This approach could be used for other hormone pairs to treat other diseases.

Hypothalamus participates in systemic metabolic processes, while high calorie intake increases immune activation in the central nervous system. Here the authors show that reduced regulatory T cells in the hypothalamus contribute to elevated immune activation in a high calorie environment, thereby prompting a potential therapy target for metabolic diseases.

This study, together with a companion manuscript, show that, in mice, weight loss as a result of GIP receptor antagonism requires, and potentiates, functional GLP-1 receptor signalling in the brain, explaining how both GIP receptor agonists and antagonists trigger weight loss through different mechanisms.

Hypothalamic melanocortin neurons control energy homoeostasis by modulating appetite. Here, the authors reveal a role for the transcription factor Tbx3 as a regulator of the peptidergic identity and function of immature and mature mouse melanocortin neurons.

Here, Miranda-Cervantes et al. identified pantothenate kinase 4 (PanK4) as a key regulator of muscle metabolism. Deleting PanK4 impairs fatty acid oxidation and glucose uptake, leading to glucose intolerance, while increasing PanK4 enhances glucose metabolism, highlighting its potential in promoting metabolic health.

The insulin inhibitory receptor (inceptor) is identified as a negative regulator of insulin and IGF1 signalling that could be targeted for β-cell regeneration in treatments for diabetes.

Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes. Here the authors show the efficacy of GLP1-based multi-agonists, and superiority of GLP1/E, for managing metabolic complications of PCOS in preclinical models, with improvement also of some reproductive traits.

The diabetogenic effect of glucagon has long overshadowed the potential of this pancreatic hormone as an endogenous satiety and anti-obesity factor. This Review discusses the role of glucagon as a beneficial endocrine factor in lipid and energy metabolism and its potential as a therapeutic agent on the basis of studies that combine the agonism of glucagon receptor and glucagon-like peptide 1 receptor.

Animal models are necessary for the discovery, validation and optimization of novel therapeutics. Here, Matthias Tschöp and colleagues consolidate the key information on the currently available animal models of obesity and diabetes mellitus and highlight the advantages, limitations and important caveats of each of these models.

The precise mechanisms that cause human obesity remain unknown. Here the authors illustrate how increased expression of Cadm1, a mediator of synapse assembly, is relevant to weight gain. Reduction of Cadm1 in multiple brain regions promoted weight loss, and these observations provide insight into the neuronal pathways contributing to obesity.

A conjugate drug consisting of GLP-1 receptor agonist and the PPARɑ/ɣ dual-agonist tesaglitazar is shown to have superior anti-diabetic effects than monotherapy.

The murine G protein-coupled receptor 83 (Gpr83) is expressed widely in the brain, but its physiological role is largely unknown. Here Müller et al.show that Gpr83 regulates systemic energy metabolism in part by modulating ghrelin signalling in the arcuate nucleus of the hypothalamus.

Johannes Beckers, Martin Hrabě de Angelis and colleagues use in vitro fertilization to demonstrate epigenetic germline inheritance of acquired metabolic disorders in mice. They show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes.

Although it affects food intake and energy partitioning, the precise role of the various forms of ghrelin and its receptor(s) in energy balance remains unclear. As described here, its specific effects on glucose homeostasis mean that it is a potential target to prevent and treat obesity and type 2 diabetes.

Extracellular vesicles (EVs) convey inter-organ communication in health and disease. Here, the authors report that adipocyte-derived EVs isolated from insulin-resistant obese but not lean male mice stimulate insulin secretion via the targeted transfer of insulinotropic proteins from adipose tissue to β-cells.

Histone deacetylases (HDACs) regulate energy metabolism in peripheral tissues, but whether HDACs expressed in the brain influence systemic metabolism is unknown. Here the authors show that hypothalamic HDAC5 expression is affected by the diet and HDAC5 regulates leptin sensitivity by deacetylating STAT3.

Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1α. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1α induction.

This study finds that inhibition of the hypothalamic melanocortin receptors increases the level of high-density lipoprotein HDL-C, a form of cholesterol, circulating in the blood stream. Uptake of HDL-C into the liver was slowed, as expression of one of the hepatic cholesterol receptors was downregulated.

Brown adipose thermogenesis increases energy expenditure and relies on uncoupling protein 1 (UCP1), however, UCP1 knock-out mice show resistance to diet-induced obesity at room temperature. Here, the authors show that this resistance relies on FGF21-signaling, inducing the browning of white adipose tissue.

A combination of single-cell approaches, lineage tracing and metabolomics is used to characterize the changes to intestinal stem cell function in the small intestine that underlie intestinal maladaptation in mice fed an obesogenic diet.

A new study used several mouse mutants to study insulin receptor function specifically in the ventromedial nucleus of the hypothalamus (VMH), and found a role for VMH insulin signaling in promoting high-fat diet–induced obesity.

β-cell dedifferentiation has emerged as a contributing mechanism in type 1 and type 2 diabetes development. Here Sachs et al. show that a pharmacological treatment that combines insulin and a GLP-1–oestrogen conjugate reverses dedifferentiation, and improves β-cell function and hyperglycaemia in diabetic mice.

Tobacco smoking and cold exposure are environmental modulators of human energy metabolism suppressing appetite and increasing energy expenditure, respectively. Here, the authors develop a novel pharmacological strategy in which they simultaneously mimic the metabolic benefits of both phenomena through small-molecule combination therapy, and show that this treatment improves metabolic health of obese mice.

In contrast to previously reported findings, M2-like polarized macrophages are not a source of catecholamines and do not contribute to browning of the fat.

Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar immune mediators, BAFF and APRIL, in modifying diet-induced weight gain and adipocyte lipid handling.

Long-term consumption of a calorie-rich diet persistently activates brain microglia. Here, the authors show that microglial activity in mouse brains oscillates daily in conjunction with feeding, and that TNFα, secreted by activated microglia, induces mitochondrial stress in satiety-promoting POMC neurons.

Metagenomic analysis of gastrointestinal bacteria sheds light on obesity.

Ghrelin stimulates food uptake by bringing about changes in mitochondrial respiration and proliferation, which are essential for activation of NPY/AgRP neurons. The effects of ghrelin are dependent on the presence of UCP2.

The genetic basis of metabolic diseases is incompletely understood. Here, by high-throughput phenotyping of 2,016 knockout mouse strains, Rozman and colleagues identify candidate metabolic genes, many of which are associated with unexplored regulatory gene networks and metabolic traits in human GWAS.

A rationally designed peptide agonist that targets three key hormone receptors reduces obesity and its complications in a manner superior to other agonists.

Emerging studies suggest that p53 is an important regulator of energy metabolism, yet there is little known about the metabolic function of this tumor suppressor in the hypothalamus. Here, authors illustrate that p53, specifically in AgRP neurons, is required for adaptation to diet-induced obesity.

In male mice with diet-induced obesity, deletion of insulin inhibitory receptor (inceptor) in the whole body, in the brain and in pancreatic β cells improves glucose homeostasis, underlining a role of inceptor in regulating glucose homeostasis in the brain and pancreas.

Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression and muscle glucose uptake.

Long-acting GIPR agonists, individually or as part of GIPR–GLP-1R co-agonists, are shown to require GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake in mice.