Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis

International audienceBACKGROUND & AIMS: Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions. Up to now, it is not clear if MAM miscommunication could have a causal role in hepatic insulin resistance and steatosis. We therefore aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment. METHODS: We analyzed hepatic ER-mitochondria interactions and calcium exchange in diet-induced obese mice in a time-dependent and reversible manner, and investigated causality in hepatic metabolic alterations by expressing a specific organelle spacer or linker in mouse liver, using adenovirus. RESULTS: Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in diet-induced obese mice. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type-2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index. CONCLUSIONS: ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could contribute to restoring metabolic homeostasis. LAY SUMMARY: The literature suggests that interactions between endoplasmic reticulum (ER) and mitochondria could play a dual role in hepatic insulin resistance and steatosis during chronic obesity. The present study reappraised time-dependent regulation of hepatic ER-mitochondria interactions and calcium exchange in diet-induced obese mice and their causal role in hepatic insulin resistance and steatosis. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be improved by nutritional strategies