insulin-producing β-cells, and type 2 diabetes (T2D) results from a combination of insulin resistance and β-cell insulin secretory defect; in the long-term, β-cell exhaustion and eventually destruction occur [...] glucose levels resulting from an impairment in insulin action and/or insulin secretion. More than 425 million individuals have diabetes worldwide and projections show this number rising to 629 million by 2045

excess ceramide accumulation that leads to impaired insulin signaling and energy homeostasis, and eventually to insulin resistance and type 2 diabetes. The ceramide species C16:0 ceramide plays a key role [...] role in the development of insulin resistance. Raichur, Brunner, and colleagues investigated if the specific inhibition of ceramide synthase 6 (CerS6) might be suitable for a drug intervention approach using [...] ceramide reduction could be an attractive target for the treatment of insulin resistance, obesity, and type 2 diabetes.

increased by fasting and a reduction of insulin/IGF signaling (IIS), an effect that is conserved from nematodes to humans. Two major "signaling nodes", Forkhead box O1 (FoxO1)- and Target Of Rapamycin Complex [...] Complex 1 (TORC1)-centered, are responsible for the effect of nutrients and IIS on the lifespan. Zaarur et al. recently found that FoxO1 and mTORC1 control the rates of lipolysis in mammalian cells by regulating [...] (ATGL). Here, they use the nematode C. elegans to show that ATGL is the common mediator of the fasting and IIS longevity effects.

synaptic formation, remodeling, neuronal migration, and development. There are two known receptors for Reelin, the very low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (ApoER2). Roberts [...] ApoER2, and VLDLR expression in the hypothalamus. They demonstrate a possible mechanism by which Reelin could influence energy homeostasis. In addition, consumption of a high fat diet blunts VLDLR and ApoER2 [...] ApoER2 expression in the hypothalamus and disrupts at least one mechanism by which Reelin acts on arcuate proopiomelanocortin neurons.

necroptotic markers in insulin resistance and T2D remains unclear. Xu, Du, and colleagues show that the loss of MLKL in mice prevents obesity-induced insulin resistance and glucose intolerance. These findings [...] Inflammation and cell death contribute to the development of type 2 diabetes (T2D). Necroptosis, a recently characterized necrosis integrated with the extrinsic apoptosis pathway, is widely viewed as a [...] findings reveal a role of MLKL in insulin sensitivity and suggest the potential involvement of necroptotic regulators in the physiopathology of T2D.

mitochondrial stress and the unfolded protein response (UPR). Plasma GDF15 levels are increased in a wide range of diseases, such as cancer, inflammation, cardiovascular disease, and during dysregulation [...] to treat metabolic disorders or cancer-induced cachexia. Indeed, body weight and food intake were reduced in obese mice and monkeys overexpressing GDF15 or administered long-acting recombinant GDF15. [...] its receptor with a monoclonal antibody improved cancer or chemotherapy-induced anorexia and weight loss in mice and/or nonhuman primates. A recent 12-week multiple ascending dose study in overweight or obese

basal metabolism, response to food restriction, and susceptibility to develop activity based-anorexia, binge eating, and metabolic syndrome in male and female offspring. They report that chronic prenatal [...] suggests that epigenetic mechanisms may be involved in initiating and maintaining EDs. While epigenetic mechanisms are known to modulate behavior and health at various stages during the life cycle, it is in the [...] 17 | November 2018 Volume 17 | November 2018 Cover Story Eating disorders (EDs) are damaging mental and metabolic illnesses that predominantly affect women. While the early origins of these disorders remain

Skeletal muscle is the main insulin-sensitive tissue for postprandial glucose disposal and for the oxidation of glucose- and lipid-based fuels. Forkhead box (FOXO) proteins play a role in the regulation of energy [...] muscle remains unclear. Lundell et al. reveal that FOXO1 and FOXO3 transcriptional activity is necessary for the regulation of glucose handling and control of inflammatory signaling in mature skeletal muscle

light chain (FTL) and ferritin heavy chain (FTH). Blankenhaus, Braza, et al. report that global Fth deletion in adult mice leads to a profound disruption of organismal Fe metabolism and redox homeostasis [...] sustain energy expenditure and thermal homeostasis. Ferritin acts as a gatekeeper of organismal Fe metabolism, coupling nutritional Fe supply to organismal energy expenditure and thermoregulation.

including the hypothalamus and the main olfactory bulb (MOB). Odor detection is one of the most important triggers to initiate food intake for most animals including humans. Mortreux and colleagues found that [...] new link between olfaction, eating behavior, and energy homeostasis. In humans, plasma PROK2 correlated negatively with type 2 diabetes, body mass index, and energy intake.

insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, LY3298176. The dual functionality of the peptide is described in preclinical in vitro and in vivo models and in clinical trials. In the latter [...] latter, LY3298176 led to decreased glucose levels and decreased body weight in healthy individuals during a multiple ascending dose study, and in a randomized, 4-week, Phase 1b trial in T2DM patients.

to hyperglycemia and systemic insulin resistance. To directly assess the role of skeletal muscle Akt on muscle growth and glucose homeostasis, Jaiswal et al. deleted Akt2 or both Akt1 and Akt2 specifically [...] alone showed no effect on muscle growth and glucose metabolism, congenital deletion of both the Akt isoforms resulted in a drastic reduction in muscle mass and a mild defect in glucose tolerance.

body weight, and glucose tolerance. Thus, they conclude that TSK in not a significant regulator of BAT thermogenesis and is unlikely to represent an effective target for preventing obesity and improving glucose [...] in brown adipose tissue (BAT) and reduce energy expenditure. In contrast, Mouchiroud et al. found that TSK-null mice are not protected against the development of obesity and do not show improvement in glucose

functions. Osteocalcin-/- mice have increased anxiety-like behavior and depression, decreased exploratory behavior, and impaired learning and memory. Given that osteocalcin is produced only by osteoblasts, [...] Khrimian et al. asked whether an impairment in osteoblast differentiation and function, as may occur in various skeletal dysplasias or with aging, could affect cognition or anxiety. Their results suggest

functions. Osteocalcin-/- mice have increased anxiety-like behavior and depression, decreased exploratory behavior, and impaired learning and memory. Given that osteocalcin is produced only by osteoblasts, [...] Khrimian et al. asked whether an impairment in osteoblast differentiation and function, as may occur in various skeletal dysplasias or with aging, could affect cognition or anxiety. Their results suggest