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

• Published in: Molecular and cellular endocrinology 2018-01, Vol.460, p.238-245
• Main Authors: Carraro, Rodrigo S., Souza, Gabriela F., Solon, Carina, Razolli, Daniela S., Chausse, Bruno, Barbizan, Roberta, Victorio, Sheila C., Velloso, Licio A.
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - metabolism; Cytokines; Diet, High-Fat; Endoplasmic Reticulum Stress; GTP Phosphohydrolases - metabolism; Hypothalamus; Hypothalamus - pathology; Hypothalamus - ultrastructure; Inflammation - pathology; Metabolism; Mice; Mitochondria - pathology; Mitochondria - ultrastructure; Neurons; Neutralization Tests; Obesity - pathology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2017.07.029

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. •Hypothalamic dysfunction in obesity results from inflammation, endoplasmic reticulum stress and mitochondrial abnormalities.•Mitochondrial abnormalities occur at a latter stage as compared with inflammation and endoplasmic reticulum stress.•Fractakine is the earliest marker of hypothalamic inflammation induced a few hours after the introduction of dietary fats.