SUMMARY Obesity and nutrient homeostasis are linked by mechanisms that are not fully elucidated. Here we describe a secreted protein, adropin, encoded by a gene, Energy Homeostasis Associated (Enho), expressed in liver and brain. Liver Enho expression is regulated by nutrition: lean C57BL/6J mice fed high-fat diet (HFD) exhibited a rapid increase, while fasting reduced expression compared to controls. However, liver Enho expression declines with diet-induced obesity (DIO) associated with 3 months of HFD or with genetically induced obesity, suggesting an association with metabolic disorders in the obese state. In DIO mice, transgenic overexpression or systemic adropin treatment attenuated hepatosteatosis and insulin resistance independently of effects on adiposity or food intake. Adropin regulated expression of hepatic lipogenic genes and adipose tissue peroxisome proliferator-activated receptor gamma, a major regulator of lipogenesis. Adropin may therefore be a factor governing glucose and lipid homeostasis, which protects against hepatosteatosis and hyperinsulinemia associated with obesity.

Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.pramlintide ͉ metreleptin ͉ adiposity ͉ synergy ͉ leptin resistance T he discovery of leptin in 1994 (1) revolutionized our understanding of the biological basis of body-weight regulation and raised hopes that this adipokine could be a breakthrough treatment for obesity. Although leptin plays a pivotal role in regulating energy homeostasis in rodents and humans, its pharmaceutical development as a stand-alone antiobesity agent has proven unsuccessful (2). Although leptin replacement elicits profound weight loss in leptindeficient (Lep ob /Lep ob ) mice and humans (3, 4), even high pharmacological doses elicit only marginal weight loss in non-leptindeficient, diet-induced obese (DIO) rodents and humans (2, 5). The obese state is thus thought to be associated with ''leptin resistance,'' wherein overweight/obese individuals become insensitive to high circulating leptin concentrations (6). The mechanistic basis for leptin resistance is poorly understood, but rodent data implicate leptin transport saturation (7), leptin receptor down-regulation (8), and reduced hypothalamic postreceptor signaling (9, 10).Amylin, a 37-aa peptide hormone cosecreted with insulin from pancreatic ␤-cells (11), binds specific receptors in the hindbrain area postrema (AP) that activate multiple central nervous system (CNS) regions to regulate both glucose and energy homeostasis (12). In obese humans, the amylin analog pramlintide elicited sustained reductions in food intake and body weight (13,14). Amylin-induced weight loss in DIO rats that was observed to be fat-specific with relative...

Trevaskis JL, Griffin PS, Wittmer C, Neuschwander-Tetri BA, Brunt EM, Dolman CS, Erickson MR, Napora J, Parkes DG, Roth JD. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice.

Here we describe a novel protein, which we have named Tanis, that is implicated in type 2 diabetes and inflammation. In Psammomys obesus, a unique polygenic animal model of type 2 diabetes and the metabolic syndrome, Tanis is expressed in the liver in inverse proportion to circulating glucose (P ‫؍‬ 0.010) and insulin levels (P ‫؍‬ 0.004) and in direct proportion with plasma triglyceride concentrations (P ‫؍‬ 0.007). Hepatic Tanis gene expression was markedly increased (3.1-fold) after a 24-h fast in diabetic but not in nondiabetic P. obesus. In addition, glucose inhibited Tanis gene expression in cultured hepatocytes (P ‫؍‬ 0.006) as well as in several other cell types (P ‫؍‬ 0.001-0.011). Thus, Tanis seems to be regulated by glucose and is dysregulated in the diabetic state. Yeast-2 hybrid screening identified serum amyloid A (SAA), an acute-phase inflammatory response protein, as an interacting protein of Tanis, and this was confirmed by Biacore experiments. SAA and other acute-phase proteins have been the focus of recent attention as risk factors for cardiovascular disease, and we contend that Tanis and its interaction with SAA may provide a mechanistic link among type 2 diabetes, inflammation, and cardiovascular disease.