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Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity

Nature Medicine volume 8, pages 179–183 (2002)Cite this article

An Erratum to this article was published on 01 March 2002

Abstract

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.

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Figure 1: Centrally administered Cpd 1 reduces food intake and body weight.
Figure 2: Cpd 2 attenuates body weight gain and adiposity in ICR mice fed the HFD.

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Acknowledgements

We thank D. Szalkowski and Z. Li for help with necropsy and J. Ronan for help with preparation of histology slides. This work was supported in part by grants from the DFG (M.Z.S.), the American Diabetes Association (Physician Scientist Training Award to E.L.A.) and NIH (S.C.W.).

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Author notes

  1. Ellen L. Air and Mathias Z. Strowski: E.L.A. and M.Z.S. contributed equally to this paper.

Authors and Affiliations

  1. Departments of Biomedical Sciences and Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Ellen L. Air

  2. Department of Molecular Endocrinology and Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey, USA

    Mathias Z. Strowski, Stacey L. Conarello, Xiao-Ming Guan & Bei B. Zhang

  3. Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Stephen C. Benoit, Kun Liu & Stephen C. Woods

  4. Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey, USA

    Gino M. Salituro

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  1. Ellen L. Air
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Correspondence to Bei B. Zhang.

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G.M. Salituro, X.-M. Guan, K. Liu & B.B. Zhang are employees and shareholders of Merck and Co.

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Air, E., Strowski, M., Benoit, S. et al. Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity. Nat Med 8, 179–183 (2002). https://doi.org/10.1038/nm0202-179

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