Mitofusin 2 in POMC Neurons Connects ER Stress with Leptin Resistance and Energy Imbalance

Abstract

SUMMARY Mitofusin 2 (Mfn2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establishes Mfn2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for Mfn2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.

Mfn2 is critical for brown adipose tissue thermogenic function

“…This could be due, at least in part, to a marked decrease in Complex I and III levels in the mitochondria from the BAT of Mfn2‐adKO animals, which dampened respiratory capacity in BAT homogenates. Mitochondrial dysfunction and reduced Complex I respiratory activity in Mfn2 defective tissues has been previously reported in conditional knockout models for POMC neurons and liver tissue (Sebastian et al , 2012; Schneeberger et al , 2013), albeit never as severe as in our Mfn2‐adKO mice. Decreased Complex I activity upon Mfn2 deficiency has also been observed in skeletal muscle, brain, and liver tissues (Sebastian et al , 2012; Schneeberger et al , 2013).…”

“…In line with this, Mfn2 deficiency has been shown to trigger ER stress at least in liver, brain, and muscle (Sebastian et al , 2012; Schneeberger et al , 2013). Confirming these observations, Mfn2 deficiency also increased ER stress markers and p‐IRE phosphorylation in BAT (Fig EV2E and F).…”

“…In mice, the whole‐body Mfn2 deficiency is lethal at mid‐gestation due to impairment of placental function (Chen et al , 2003). However, transgenic mice with tissue‐specific ablations of Mfn2 have unveiled the multiple metabolic roles of Mfn2 (Sebastian et al , 2012; Schneeberger et al , 2013). The liver‐specific deletion of Mfn2 led to systemic metabolic abnormalities, such glucose intolerance and enhanced hepatic gluconeogenesis (Sebastian et al , 2012).…”

“…The liver‐specific deletion of Mfn2 led to systemic metabolic abnormalities, such glucose intolerance and enhanced hepatic gluconeogenesis (Sebastian et al , 2012). In brain, POMC neuron‐specific deletion of Mfn2 induced hyperphagia and obesity while reducing energy expenditure (Schneeberger et al , 2013). Many of these effects have been attributed to the ability of Mfn2 to mediate not only mitochondria–mitochondria contacts, but also to influence the interaction of mitochondria with other cellular membrane organelles.…”

“…Many of these effects have been attributed to the ability of Mfn2 to mediate not only mitochondria–mitochondria contacts, but also to influence the interaction of mitochondria with other cellular membrane organelles. For example, Mfn2 has a critical role in the maintenance of mitochondria–endoplasmic reticulum (ER) interactions (de Brito & Scorrano, 2008; Cosson et al , 2012; Filadi et al , 2015), and ablation of Mfn2 triggered ER stress in virtually all models tested (Sebastian et al , 2012; Schneeberger et al , 2013). …”