Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response

Seul Gi Kang,Min Jeong Choi,Saet-Byel Jung,Hyo Kyun Chung,Joon Young Chang,Jung Tae Kim,Yea Eun Kang,Ju Hee Lee,Hyun Jung Hong,Sang Mi Jun,Hyun-Joo Ro,Jae Myoung Suh,Hail Kim,Johan Auwerx,Hyon-Seung Yi,Minho Shong

doi:10.1016/j.isci.2021.102181

Abstract

SummaryPerturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. LKO mice are highly insulin sensitive and resistant to diet-induced obesity. The hepatocytes of LKO mice secrete large quantities of metabokines, including GDF15 and FGF21, which confer metabolic benefits. We evaluated the metabolic phenotypes of LKO mice with global deficiency of GDF15 or FGF21 and show that GDF15 regulates body and fat mass and prevents diet-induced hepatic steatosis, whereas FGF21 upregulates insulin sensitivity, energy expenditure, and thermogenesis in white adipose tissue. This study reveals that the mitochondrial integrated stress response (ISRmt) in liver mediates metabolic adaptation through hepatic metabokines.

Highlights

Mitochondria are frequently exposed to conditions of stress, which induce mitochondrial quality control mechanisms that are essential to maintain mitochondrial function (Sorrentino et al, 2018)
Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation
Liverspecific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response

Summary

Introduction

Mitochondria are frequently exposed to conditions of stress, which induce mitochondrial quality control mechanisms that are essential to maintain mitochondrial function (Sorrentino et al, 2018). Hepatocyte mitochondria are essential for the maintenance of metabolic plasticity and flexibility (Koliaki and Roden, 2016), and consistent with this, recent studies have shown that mouse models of hepatic mitochondrial dysfunction have alterations in their systemic metabolism, including changes in insulin sensitivity, energy expenditure (EE), and their response to diet-induced obesity (Cho et al, 2017; Kulkarni et al, 2016; Lee et al, 2017; Pospisilik et al, 2007) These findings suggest that the hepatic adaptation to mitochondrial stress may affect systemic energy metabolism through alterations to substrate utilization in the liver and the induction of metabokines that are secreted and can modulate energy metabolism. The significance of these hepatic metabokines in the control of systemic metabolism has not been studied extensively

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