Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes.
The molecular link between obesity and beta cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of insulin receptor substrate 2 (Irs2) in mouse pancreas beta cells and parts of the brain--including the hypothalamus--increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional beta cells expressing Irs2 repopulated the pancreas, restoring sufficient beta cell function to compensate for insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult beta cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.
Howard Hughes Medical Institute Children's Hospital, Division of Endocrinology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Xueying
X
Lin
Akiko
A
Taguchi
Sunmin
S
Park
Jake A
JA
Kushner
Fan
F
Li
Yedan
Y
Li
Morris F
MF
White
D000818:Animals; D001835:Body Weight; D001921:Brain / Q000166:cytology / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004032:Diet; D004435:Eating; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D015398:Signal Transduction / Q000502:physiology*
C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D005947:Glucose