Hypothalamic glycogen synthase kinase 3β has a central role in the regulation of food intake and glucose metabolism

Biochem J. 2012 Oct 1;447(1):175-84. doi: 10.1042/BJ20120834.

Abstract

GSK3β (glycogen synthase kinase 3β) is a ubiquitous kinase that plays a key role in multiple intracellular signalling pathways, and increased GSK3β activity is implicated in disorders ranging from cancer to Alzheimer's disease. In the present study, we provide the first evidence of increased hypothalamic signalling via GSK3β in leptin-deficient Lep(ob/ob) mice and show that intracerebroventricular injection of a GSK3β inhibitor acutely improves glucose tolerance in these mice. The beneficial effect of the GSK3β inhibitor was dependent on hypothalamic signalling via PI3K (phosphoinositide 3-kinase), a key intracellular mediator of both leptin and insulin action. Conversely, neuron-specific overexpression of GSK3β in the mediobasal hypothalamus exacerbated the hyperphagia, obesity and impairment of glucose tolerance induced by a high-fat diet, while having little effect in controls fed standard chow. These results demonstrate that increased hypothalamic GSK3β signalling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arcuate Nucleus of Hypothalamus / enzymology
  • Arcuate Nucleus of Hypothalamus / physiology
  • Base Sequence
  • DNA Primers / genetics
  • Diet, High-Fat / adverse effects
  • Eating / physiology*
  • Glucose / metabolism*
  • Glucose Intolerance / enzymology
  • Glucose Intolerance / etiology
  • Glycogen Synthase Kinase 3 / deficiency
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Hypothalamus / enzymology*
  • Hypothalamus / physiology
  • Leptin / deficiency
  • Leptin / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / enzymology
  • Obesity / etiology
  • Signal Transduction
  • Weight Gain / physiology

Substances

  • DNA Primers
  • Leptin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Glucose