Nutrient responsive nesfatin-1 regulates energy balance and induces glucose-stimulated insulin secretion in rats.

Nesfatin-1 is a recently discovered anorexigen, and we first reported nesfatin-like immunoreactivity in the pancreatic ß-cells. The aim of this study was to characterize the effects of nesfatin-1 on whole-body energy homeostasis, insulin secretion, and glycemia. The in vivo effects of continuous peripheral delivery of nesfatin-1 using osmotic minipumps on food intake and substrate partitioning were examined in ad libitum-fed male Fischer 344 rats. The effects of nesfatin-1 on glucose-stimulated insulin secretion (GSIS) were examined in isolated pancreatic islets. L6 skeletal muscle cells and isolated rat adipocytes were used to assess the effects of nesfatin-1 on basal and insulin-mediated glucose uptake as well as on major steps of insulin signaling in these cells. Nesfatin-1 reduced cumulative food intake and increased spontaneous physical activity, whole-body fat oxidation, and carnitine palmitoyltransferase I mRNA expression in brown adipose tissue but did not affect uncoupling protein 1 mRNA in the brown adipose tissue. Nesfatin-1 significantly enhanced GSIS in vivo during an oral glucose tolerance test and improved insulin sensitivity. Although insulin-stimulated glucose uptake in L6 muscle cells was inhibited by nesfatin-1 pretreatment, basal and insulin-induced glucose uptake in adipocytes from nesfatin-1-treated rats was significantly increased. In agreement with our in vivo results, nesfatin-1 enhanced GSIS from isolated pancreatic islets at both normal (5.6 mM) and high (16.7 mM), but not at low (2 mM), glucose concentrations. Furthermore, nesfatin-1/nucleobindin 2 release from rat pancreatic islets was stimulated by glucose. Collectively, our data indicate that glucose-responsive nesfatin-1 regulates insulin secretion, glucose homeostasis, and whole-body energy balance in rats.

High-fat diet increases thyrotropin and oxygen consumption without altering circulating 3,5,3'-triiodothyronine (T3) and thyroxine in rats: the role of iodothyronine deiodinases, reverse T3 production, and whole-body fat oxidation.

This study investigated the effects of obesity induced by high-fat (HF) diet on thyroid function and whole-body energy balance. To accomplish that, we assessed the effects of 8 wk of HF diet on several parameters of hypothalamus-pituitary-thyroid axis function. Serum total T(4) and T(3), rT(3), and TSH, the activity of type 1 and type 2 deiodinases in central and peripheral tissues were determined. Also, we measured in vivo energy balance, substrate partitioning, and markers of leptin resistance. Here we provide novel evidence that prolonged positive energy balance acquired by feeding a HF diet induced hyperactivation of the hypothalamus-pituitary-thyroid axis, which was characterized by 2.24-, 1.6-, and 3.7-fold elevations in hypothalamic TRH expression, thyroid iodide uptake, and serum TSH, respectively. Serum T(4) and T(3) were normal together with augmented deiodinase type 1 activity in liver (1.3-fold) and kidney (1.2-fold) and increased (1.5-fold) serum rT3 in HF rats. Despite no increase in circulating levels of T(3) and T(4), whole-body oxygen consumption was increased, and substrate metabolism was shifted toward fat oxidation in HF rats. These in vivo metabolic adjustments were mainly driven by the fat content of the diet. Furthermore, spontaneous dark cycle physical activity was reduced by 30% in rats fed a HF diet, which limited energy expenditure and favored the development of obesity. Our findings provide new insight into the endocrine and physiological mechanisms that underlie the alterations in thyroid hormone availability, energy balance, and metabolic partitioning in HF diet-induced obesity.

Direct interaction between myocyte enhancer factor 2 (MEF2) and protein phosphatase 1alpha represses MEF2-dependent gene expression.

The myocyte enhancer factor 2 (MEF2) transcription factors play important roles in neuronal, cardiac, and skeletal muscle tissues. MEF2 serves as a nuclear sensor, integrating signals from several signaling cascades through protein-protein interactions with kinases, chromatin remodeling factors, and other transcriptional regulators. Here, we report a novel interaction between the catalytic subunit of protein phosphatase 1alpha (PP1alpha) and MEF2. Interaction occurs within the nucleus, and binding of PP1alpha to MEF2 potently represses MEF2-dependent transcription. The interaction utilizes uncharacterized domains in both PP1alpha and MEF2, and PP1alpha phosphatase activity is not obligatory for MEF2 repression. Moreover, a MEF2-PP1alpha regulatory complex leads to nuclear retention and recruitment of histone deacetylase 4 to MEF2 transcription complexes. PP1alpha-mediated repression of MEF2 overrides the positive influence of calcineurin signaling, suggesting PP1alpha exerts a dominant level of control over MEF2 function. Indeed, PP1alpha-mediated repression of MEF2 function interferes with the prosurvival effect of MEF2 in primary hippocampal neurons. The PP1alpha-MEF2 interaction constitutes a potent locus of control for MEF2-dependent gene expression, having potentially important implications for neuronal cell survival, cardiac remodeling in disease, and terminal differentiation of vascular, cardiac, and skeletal muscle.