There is an Erratum (March 2002) associated with this Article.
Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity
Ellen L. Air1, 5, Mathias Z. Strowski2, 5, Stephen C. Benoit3, Stacey L. Conarello2, Gino M. Salituro4, Xiao-Ming Guan2, Kun Liu3, Stephen C. Woods3
& Bei B. Zhang2
1
Departments of Biomedical Sciences and Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
2
Department of Molecular Endocrinology and Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey, USA
3
Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
4
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey, USA
5
E.L.A. and M.Z.S. contributed equally to this paper.
Obesity and insulin resistance are major risk factors for a number of metabolic disorders, such as type 2 diabetes mellitus1,
2. Insulin has been suggested to function as one of the adiposity signals to the brain for modulation of energy balance. Administration of insulin into the brain reduces food intake and body weight3,
4,
5, and mice with a genetic deletion of neuronal insulin receptors are hyperphagic and obese6. However, insulin is also an anabolic factor; when administered systemically, pharmacological levels of insulin are associated with body weight gain in patients7. In this study, we investigated the efficacy and feasibility of small molecule insulin mimetic compounds8,
9 to regulate key parameters of energy homeostasis. Central intracerebroventricular (i.c.v.) administration of an insulin mimetic resulted in a dose-dependent reduction of food intake and body weight in rats, and altered the expression of hypothalamic genes known to regulate food intake and body weight. Oral administration of a mimetic in a mouse model of high-fat diet-induced obesity reduced body weight gain, adiposity and insulin resistance. Thus, insulin mimetics have a unique advantage over insulin in the control of body weight and hold potential as a novel anti-obesity treatment.
