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Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity.

Abstract：

:Hypothalamic dysfunction is a common feature of experimental obesity. Studies have identified at least three mechanisms involved in the development of hypothalamic neuronal defects in diet-induced obesity: i, inflammation; ii, endoplasmic reticulum stress; and iii, mitochondrial abnormalities. However, which of these mechanisms is activated earliest in response to the consumption of large portions of dietary fats is currently unknown. Here, we used immunoblot, real-time PCR, mitochondrial respiration assays and transmission electron microscopy to evaluate markers of inflammation, endoplasmic reticulum stress and mitochondrial abnormalities in the hypothalamus of Swiss mice fed a high-fat diet for up to seven days. In the present study we show that the expression of the inflammatory chemokine fractalkine was the earliest event detected. Its hypothalamic expression increased as early as 3 h after the introduction of a high-fat diet and was followed by the increase of cytokines. GPR78, an endoplasmic reticulum chaperone, was increased 6 h after the introduction of a high-fat diet, however the actual triggering of endoplasmic reticulum stress was only detected three days later, when IRE-1α was increased. Mitofusin-2, a protein involved in mitochondrial fusion and tethering of mitochondria to the endoplasmic reticulum, underwent a transient reduction 24 h after the introduction of a high-fat diet and then increased after seven days. There were no changes in hypothalamic mitochondrial respiration during the experimental period, however there were reductions in mitochondria/endoplasmic reticulum contact sites, beginning three days after the introduction of a high-fat diet. The inhibition of TNF-α with infliximab resulted in the normalization of mitofusin-2 levels 24 h after the introduction of the diet. Thus, inflammation is the earliest mechanism activated in the hypothalamus after the introduction of a high-fat diet and may play a mechanistic role in the development of mitochondrial abnormalities in diet-induced obesity.

journal_name

Mol Cell Endocrinol

journal_title

Molecular and cellular endocrinology

authors

Carraro RS,Souza GF,Solon C,Razolli DS,Chausse B,Barbizan R,Victorio SC,Velloso LA

doi

10.1016/j.mce.2017.07.029

subject

Has Abstract

pub_date

2018-01-15 00:00:00

pages

238-245

eissn

0303-7207

issn

1872-8057

pii

S0303-7207(17)30402-1

journal_volume

460

pub_type

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Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity.