Inflammation of the hypothalamus leads to defective pancreatic islet function.
Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic β-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic β-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.
Laboratory of Cell Signaling, of Campinas, 13084-970 Sao Paulo, Brazil.
Vivian C
VC
Calegari
Adriana S
AS
Torsoni
Emerielle C
EC
Vanzela
Eliana P
EP
Araújo
Joseane
J
Morari
Claudio C
CC
Zoppi
Lourenço
L
Sbragia
Antonio C
AC
Boschero
Lício A
LA
Velloso
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D007027:Hypothalamic Diseases / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013229:Stearic Acids / Q000009:adverse effects / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000494:pharmacology
D004041:Dietary Fats; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D013229:Stearic Acids; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C031183:stearic acid
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