Original Article Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle Effects of Type 2 Diabetes, Obesity, Weight Loss, and the Regulatory Role of Tumor Necrosis Factor  and Interleukin-6 Daniel Bach, 1 Deborah Naon, 1 Sara Pich, 1 Francesc X. Soriano, 1 Nathalie Vega, 2 Jennifer Rieusset, 2 Martine Laville, 2 Christelle Guillet, 3 Yves Boirie, 3 Harriet Wallberg-Henriksson, 4 Melania Manco, 5 Menotti Calvani, 5 Marco Castagneto, 5 Manuel Palacı ´n, 1 Geltrude Mingrone, 5 Juleen R. Zierath, 4 Hubert Vidal, 2 and Antonio Zorzano 1 The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 (Mfn2). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochon- drial metabolism and intracellular signaling. The poten- tial for regulation of human Mfn2 gene expression in vivo is largely unknown. Based on the presence of mitochondrial dysfunction in insulin-resistant condi- tions, we have examined whether Mfn2 expression is dysregulated in skeletal muscle from obese or nonobese type 2 diabetic subjects, whether muscle Mfn2 expres- sion is regulated by body weight loss, and the potential regulatory role of tumor necrosis factor (TNF) or interleukin-6. We show that mRNA concentration of Mfn2 is decreased in skeletal muscle from both male and female obese subjects. Muscle Mfn2 expression was also reduced in lean or in obese type 2 diabetic patients. There was a strong negative correlation between the Mfn2 expression and the BMI in nondiabetic and type 2 diabetic subjects. A positive correlation between the Mfn2 expression and the insulin sensitivity was also detected in nondiabetic and type 2 diabetic subjects. To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion. Mean ex- pression of muscle Mfn2 mRNA increased threefold after reduction in body weight, and a positive correla- tion between muscle Mfn2 expression and insulin sen- sitivity was again detected. In vitro experiments revealed an inhibitory effect of TNF or interleukin-6 on Mfn2 expression in cultured cells. We conclude that body weight loss upregulates the expression of Mfn2 mRNA in skeletal muscle of obese humans, type 2 diabetes downregulates the expression of Mfn2 mRNA in skeletal muscle, Mfn2 expression in skeletal muscle is directly proportional to insulin sensitivity and is inversely proportional to the BMI, TNF and interleu- kin-6 downregulate Mfn2 expression and may partici- pate in the dysregulation of Mfn2 expression in obesity or type 2 diabetes, and the in vivo modulation of Mfn2 mRNA levels is an additional level of regulation for the control of muscle metabolism and could provide a mo- lecular mechanism for alterations in mitochondrial function in obesity or type 2 diabetes. Diabetes 54: 2685–2693, 2005 M itochondrial metabolism is altered in skeletal muscle during insulin-resistant states such as type 2 diabetes or obesity. Human type 2 diabetes is associated with reduced capacity to oxidize glucose in the presence of insulin and, more importantly, to oxidize fatty acid in various conditions (1,2). A significant decrease in gene expression of subunits participating in complexes I–IV of the mitochondrial elec- tron transport chain was observed in skeletal muscle of type 2 diabetic patients (3,4). Reduced glucose oxidation, decreased pyruvate dehydrogenase activity, and enhanced pyruvate dehydrogenase kinase have also been evidenced in skeletal muscle from diabetic rats (5–7). Similarly, experimental diabetes in rats reduces gene expression of From the 1 Departament de Bioquı ´mica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IRB-PCB, Parc Cientı ´fic de Barcelona, Barcelona, Spain; the 2 Institut National de la Sante ´ et de la Recherche Me ´ dicale Unite ´ -449 and Centre de Recherche en Nutrition Humaine de Lyon, Faculte ´ de Me ´ decine R.T.H., Laennec Lyon, France; the 3 Unite du Metabo- lisme Proteino-Energetique, UMR Universite d’Auvergne/INRA, CRNH, Centre Hospitalier Universitaire, Clermont-Ferrand, France; the 4 Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden; and the 5 Istituto di Medicina Interna, Facolta ` di Medicina e Chirurgia, Universita ` Cattolica, Roma, Italy. Address correspondence and reprint requests to Dr. Antonio Zorzano, Universitat de Barcelona, Departament de Bioquı´mica i Biologia Molecular, Facultat de Biologia, Avda. Diagonal 645, Barcelona, Spain, 08071. E-mail: azorzano@pcb.ub.es. Received for publication 7 January 2005 and accepted in revised form 1 June 2005. BPD, bilio-pancreatic diversion; Mfn2, mitofusin-2; TNF, tumor necrosis factor. © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES, VOL. 54, SEPTEMBER 2005 2685