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Choi SJ, Kim F, Schwartz MW, Wisse BE. Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids. Am J Physiol Endocrinol Metab 298: E1122-E1130, 2010. First published March 30, 2010; doi:10.1152/ajpendo.00006.2010.-Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1-7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNF␣, as judged by induction of IB␣ (3-to 5-fold) and IL-6 (3-to 7-fold) mRNA and p-IB␣ protein, and TNF␣ pretreatment reduced insulin-mediated p-Akt activation by 30% (P Ͻ 0.05). By comparison, neither mixed saturated fatty acid (100, 250, or 500 M for Յ6 h) nor palmitate exposure alone (200 M for Յ24 h) caused inflammatory activation or insulin resistance in cultured hypothalamic neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells. obesity; cytokine; hypothalamus DIET-INDUCED OBESITY (DIO) is caused by high-fat (HF) feeding in rodent models and is associated with low-grade systemic inflammatory responses. In both humans (20) and animal models (13), DIO is associated with increased circulating inflammatory markers such as tumor necrosis factor-␣ (TNF␣) and interleukin-6 (IL-6). In addition, white adipose tissue (WAT) becomes infiltrated by macrophages as DIO progresses, leading to increased expression and secretion of inflammatory mediators in WAT (26). Circulating cytokines (11) as well as nutrient excess from exposure to fatty acids (13, 14) also activate intracellular inflammation in a cell-autonomous manner. In liver, muscle, adipocytes, and endothelial cells, for example, inflammation can arise from intracellular processes ranging from mitochondrial dysfunction and reactive oxygen species formation to endoplasmic reticulum (ER) stress and the associated unfolded protein response. Among the key...

Choi SJ, Yablonka-Reuveni Z, Kaiyala KJ, Ogimoto K, Schwartz MW, Wisse BE. Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice. Am J Physiol Endocrinol Metab 300: E1031-E1037, 2011. First published March 22, 2011; doi:10.1152/ajpendo.00656.2010.-Myostatin deficiency causes dramatically increased skeletal muscle mass and reduced fat mass. Previously, myostatin-deficient mice were reported to have unexpectedly low total energy expenditure (EE) after normalizing to body mass, and thus, a metabolic cause for low fat mass was discounted. To clarify how myostatin deficiency affects the control of body fat mass and energy balance, we compared rates of oxygen consumption, body composition, and food intake in young myostatindeficient mice relative to wild-type (WT) and heterozygous (HET) controls. We report that after adjusting for total body mass using regression analysis, young myostatin-deficient mice display significantly increased EE relative to both WT (ϩ0.81 Ϯ 0.28 kcal/day, P ϭ 0.004) and HET controls (ϩ0.92 Ϯ 0.31 kcal/day, P ϭ 0.005). Since food intake was not different between groups, increased EE likely accounts for the reduced body fat mass (KO: 8.8 Ϯ 1.1% vs. WT: 14.5 Ϯ 1.3%, P ϭ 0.003) and circulating leptin levels (KO: 0.7 Ϯ 0.2 ng/ml vs. WT: 1.9 Ϯ 0.3 ng/ml, P ϭ 0.008). Interestingly, the observed increase in adjusted EE in myostatin-deficient mice occurred despite dramatically reduced ambulatory activity levels (Ϫ50% vs. WT, P Ͻ 0.05). The absence of hyperphagia together with increased EE in myostatin-deficient mice suggests that increased leptin sensitivity may contribute to their lean phenotype. Indeed, leptin-induced anorexia (KO: Ϫ17 Ϯ 1.2% vs. WT: Ϫ5 Ϯ 0.3%) and weight loss (KO: Ϫ2.2 Ϯ 0.2 g vs. WT: Ϫ1.6 Ϯ 0.1, P Ͻ 0.05) were increased in myostatin-deficient mice compared with WT controls. We conclude that increased EE, together with increased leptin sensitivity, contributes to low fat mass in mice lacking myostatin. energy balance; locomotor activity; body fat; insulin sensitivity MYOSTATIN, a member of the transforming growth factor-␤ family, is a paracrine factor that regulates skeletal muscle size and growth by favoring muscle atrophy and inhibiting anabolic signaling (12, 15). In mice (22) and humans (30), homozygous loss-of-function mutation of the myostatin gene causes a phenotype characterized by dramatic, whole body skeletal muscle hypertrophy and hyperplasia. Initial characterization of the energy homeostasis phenotype of myostatin-null mice revealed unexpected findings, suggesting a role for myostatin in the control of energy balance beyond its effect on skeletal muscle. Mature myostatin-null mice were found to have reduced body fat accumulation with age (23). Because energy expenditure (EE; normalized to body weight or lean body mass) in these animals was decreased relative to wild-type (WT) controls, suggestive of increased metabolic efficiency, the low-body fat phenotype remained unexplained (11, 23). A subsequent, extensive analysi...