Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome

• Published in: Endocrinology (Philadelphia) 2008-05, Vol.149 (5), p.2138-2148
• Main Authors: Bingham, Nathan C, Anderson, Kimberly K, Reuter, Anne L, Stallings, Nancy R, Parker, Keith L
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adiposity - genetics; Animals; Arcuate nucleus; Artificial chromosomes; Bacterial artificial chromosomes; Biological and medical sciences; Body Composition - genetics; Body Weight - genetics; Cre recombinase; Diet; Dyslipidemia; Eating - genetics; Endocrine System - physiology; Energy balance; Energy Metabolism - genetics; Fatty liver; Female; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Glucose tolerance; High fat diet; Homeostasis; Homeostasis - genetics; Hypothalamus; Hypothalamus (ventromedial); Integrases - genetics; Leptin receptors; Low fat diet; Male; Medical sciences; Metabolic diseases; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - genetics; Mice; Mice, Knockout; Miscellaneous; Neurons; Neurons - metabolism; Nutrient deficiency; Organ Specificity; Other metabolic disorders; Receptors; Receptors, Leptin - genetics; Receptors, Leptin - metabolism; Steatosis; Steroidogenic factor 1; Ventromedial Hypothalamic Nucleus - metabolism; Vertebrates: endocrinology; Weaning
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-1200

Leptin, an adipocyte-derived hormone, has emerged as a critical regulator of energy homeostasis. The leptin receptor (Lepr) is expressed in discrete regions of the brain; among the sites of highest expression are several mediobasal hypothalamic nuclei known to play a role in energy homeostasis, including the arcuate nucleus, the ventromedial hypothalamic nucleus (VMH), and the dorsomedial hypothalamic nucleus. Although most studies have focused on leptin’s actions in the arcuate nucleus, the role of Lepr in these other sites has received less attention. To explore the role of leptin signaling in the VMH, we used bacterial artificial chromosome transgenesis to target Cre recombinase to VMH neurons expressing steroidogenic factor 1, thereby inactivating a conditional Lepr allele specifically in steroidogenic factor 1 neurons of the VMH. These knockout (KO) mice, designated Lepr KOVMH, exhibited obesity, particularly when challenged with a high-fat diet. On a low-fat diet, Lepr KOVMH mice exhibited significantly increased adipose mass even when their weights were comparable to wild-type littermates. Furthermore, these mice exhibited a metabolic syndrome including hepatic steatosis, dyslipidemia, and hyperleptinemia. Lepr KOVMH mice were hyperinsulinemic from the age of weaning and eventually developed overt glucose intolerance. These data define nonredundant roles of the Lepr in VMH neurons in energy homeostasis and provide a model system for studying other actions of leptin in the VMH.