Insulin-Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity

• Published in: Cell reports (Cambridge) 2016-12, Vol.17 (10), p.2512-2521
• Main Authors: Hausen, A. Christine, Ruud, Johan, Jiang, Hong, Hess, Simon, Varbanov, Hristo, Kloppenburg, Peter, Brüning, Jens C.
• Format: Article
• Language: English
• Subjects: Animals; Diet, High-Fat; energy homeostasis; Energy Metabolism - drug effects; Glucose - metabolism; glucose homeostasis; Humans; Hypothalamic Hormones - genetics; Hypothalamus - metabolism; Insulin - administration & dosage; Insulin - metabolism; insulin receptor; Insulin Resistance - genetics; insulin signaling; lateral hypothalamus; Locomotion - drug effects; locomotor activity; MCH; Melanins - genetics; Mice; Neurons - drug effects; Neurons - pathology; Obesity - drug therapy; Obesity - metabolism; Obesity - pathology; Phosphatidylinositol 3-Kinases - genetics; PI3K; Pituitary Hormones - genetics; selective insulin resistance
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.11.030

Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IRΔMCH) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IRΔMCH mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance. [Display omitted] •Insulin promotes PI3 kinase signaling in MCH neurons and increases excitability•Obesity promotes insulin signaling in MCH neurons•Insulin action on MCH neurons controls locomotor activity and insulin sensitivity•Acute activation of MCH neurons impairs locomotor activity Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus regulate energy and glucose homeostasis. Hausen et al. report that insulin activates MCH neurons and that insulin signaling in these neurons is increased under obese conditions. This contributes to the manifestation of impaired locomotor activity and insulin sensitivity in obesity.