A mouse model of human mitofusin-2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Abstract

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.

Mitochondrial fractions located in the cytoplasmic and peridroplet areas of white adipocytes have distinct roles

“…However, these studies were not conducted with WAs in vivo and two comportments in the mitochondria. Recently, Mann reported that the p.Arg707Trp mutation in MFN2 caused severe upper body overgrowth and insulin resistance in humans and adipose‐specific mitochondrial abnormalities, but no apparent systemic metabolic disorder, in mice [32]. This result suggested that MFN2 is involved in regulating mitochondrial function in WA, however, its influence appear species‐specific.…”

The MFN2 Q367H variant from a patient with late-onset distal myopathy reveals a novel pathomechanism connected to mtDNA-mediated inflammation

“…Characterized by weakness, numbness and pain in the distal regions of the body, CMT2A is often an early-onset progressively-worsening disease (8). In addition to peripheral neuropathy, patients with certain MFN2 variants can present with other pathogenic phenotypes, such as myopathy (9)(10)(11), optic atrophy, sensorineural hearing loss, ataxia (12), or multiple symmetric lipomatosis (MSL) (13)(14)(15). How and why different variants in MFN2 lead mechanistically to pathology is not fully understood, though it is likely not as simple as reduced mitochondrial fusion (16).…”