title: The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity.
abstract: 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.
authors.affiliation: From the Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland.
authors.forename: Laurène
authors.initials: L
authors.lastname: Vetterli
authors.affiliation: From the Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland.
authors.forename: Stefania
authors.initials: S
authors.lastname: Carobbio
authors.affiliation: From the Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Frigerio
authors.affiliation: From the Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland.
authors.forename: Melis
authors.initials: M
authors.lastname: Karaca
authors.affiliation: From the Department of Cell Physiology and Metabolism and Faculty Diabetes Center, Geneva University Medical Centre, 1211 Geneva 4, Switzerland Pierre.Maechler@unige.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
mesh_terms: D000818:Animals; D001481:Basal Metabolism; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D018149:Glucose Intolerance; D005969:Glutamate Dehydrogenase / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D005969:Glutamate Dehydrogenase
keywords: beta cell (B-cell); insulin secretion; obesity; transgenic mice; type 2 diabetes