The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

J Biol Chem. 2016 Jun 17;291(25):13063-75. doi: 10.1074/jbc.M115.707448. Epub 2016 May 2.


Efficient energy storage in adipose tissues requires optimal function of the insulin-producing β-cell, whereas its dysfunction promotes diabetes. The associated paradox related to β-cell efficiency is that excessive accumulation of fat in adipose tissue predisposes for type 2 diabetes. Insulin exocytosis is regulated by intracellular metabolic signal transduction, with glutamate dehydrogenase playing a key role in the amplification of the secretory response. Here, we used mice with β-cell-selective glutamate dehydrogenase deletion (βGlud1(-/-)), lacking an amplifying pathway of insulin secretion. As opposed to control mice, βGlud1(-/-) animals fed a high calorie diet maintained glucose tolerance and did not develop diet-induced obesity. Islets of βGlud1(-/-) mice did not increase their secretory response upon high calorie feeding, as did islets of control mice. Inhibited adipose tissue expansion observed in knock-out mice correlated with lower expression of genes responsible for adipogenesis. Rather than being efficiently stored, lipids were consumed at a higher rate in βGlud1(-/-) mice compared with controls, in particular during food intake periods. These results show that reduced β-cell function prior to high calorie feeding prevented diet-induced obesity.

Keywords: beta cell (B-cell); insulin secretion; obesity; transgenic mice; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basal Metabolism
  • Cells, Cultured
  • Diet, High-Fat / adverse effects*
  • Glucose Intolerance
  • Glutamate Dehydrogenase / genetics
  • Insulin-Secreting Cells / physiology*
  • Lipid Metabolism
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / etiology*
  • Obesity / pathology
  • Signal Transduction*


  • Glutamate Dehydrogenase