Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight

Abstract

SUMMARY We found that exposure of adult animals to caloriedense foods rapidly abolished expression of mitofusin 2 (Mfn2), a gene promoting mitochondrial fusion and mitochondrion-endoplasmic reticulum interactions, in white and brown fat. Mfn2 mRN was also robustly lower in obese human subjects compared with lean controls. Adipocyte-specific knockdown of Mfn2 in adult mice led to increased food intake, adiposity, and impaired glucose metabolism on standard chow as well as on a diet with high calorie content. The body weight and adiposity of mature adipocyte-specific Mfn2 knockout mice on a standard diet were similar to those of control mice on a high-fat diet. The transcriptional profile of the adipose tissue in adipocyte-specific Mfn2 knockout mice was consistent with adipocyte proliferation, increased lipogenesis at the tissue level, and decreased glucose utilization at the systemic level. These observations suggest a possible crucial role for mitochondrial dynamics in adipocytes in initiating systemic metabolic dysregulation.

The Role of Adipose Tissue Mitochondria: Regulation of Mitochondrial Function for the Treatment of Metabolic Diseases

“…In addition, mitochondrial fission by protein kinase A (PKA)-dependent phosphorylation of DRP1 at serine 600 is essential for the thermogenesis of the brown adipocytes, and impairment of this regulatory pathway disrupts brown adipocyte function [70]. It has been reported that reduced expression of MFN2 is associated with the reduced function of mitochondria in subcutaneous and visceral adipose tissues of obese subjects [109]. Furthermore, adipocyte-selective inducible deletion of Mfn2 in mice leads to obesity and insulin resistance [109].…”

“…It has been reported that reduced expression of MFN2 is associated with the reduced function of mitochondria in subcutaneous and visceral adipose tissues of obese subjects [109]. Furthermore, adipocyte-selective inducible deletion of Mfn2 in mice leads to obesity and insulin resistance [109]. The role of mitochondrial dynamics in adipocyte metabolism has not been thoroughly elucidated, and further studies are required to understand the novel regulatory mechanisms of mitochondria in adipocytes.…”

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

“…Several transcriptional factors including PPARα, PPARδ and PPARγ in the skeletal muscle involved in enhancing insulin sensitivity, glucose tolerance, energy expenditure, and lipid metabolism . Activation of these transcriptional factors enhanced mitochondrial biogenesis leads to dramatically increased endurance, ameliorated insulin resistance in obesity, and type 2 diabetes . It has been known that mitochondrial dysfunction and cellular oxidative stress induced by excess energy states and elevations in circulating free fatty acid (FFA) are associated with insulin resistance in skeletal muscle .…”

Reduced electron transport chain complex I protein abundance and function in Mfn2‐deficient myogenic progenitors lead to oxidative stress and mitochondria swelling

“…27 It has been reported that Mfn2 knockout or mutation impairs thermogenesis of brown adipocytes, promotes adiposity, and leads to type 2A Charcot-Marie-Tooth disease. [28][29][30] In cultured muscle cells, Mfn2 has been reported to modulate cell respiration, substrate oxidation, and expression of oxidative phosphorylation subunit proteins. 24 In C2C12 and L6E9 myoblast cell lines, Mfn2 levels increase after differentiation, to promote mitochondrial activity and facilitate myocyte fusion.…”