CMT Type 2A/expression of Mfn2: Type 2 Diabetes, Obesity, Weight Loss

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Diabetes. 2005 Sep;54(9):2685-93.

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 {alpha} and

Interleukin-6.

Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, Laville M,

Guillet C, Boirie Y, Wallberg-Henriksson H, Manco M, Calvani M,

Castagneto M, Palacin M, Mingrone G, Zierath JR, Vidal H, Zorzano A.

Universitat de Barcelona, Departament de Bioquimica i Biologia

Molecular, Facultat de Biologia, Avda. Diagonal 645, Barcelona,

Spain, 08071.

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

mitochondrial metabolism and intracellular signaling. The potential

for regulation of human Mfn2 gene expression in vivo is largely

unknown. Based on the presence of mitochondrial dysfunction in

insulin-resistant conditions, we have examined whether Mfn2

expression is dysregulated in skeletal muscle from obese or nonobese

type 2 diabetic subjects, whether muscle Mfn2 expression is regulated

by body weight loss, and the potential regulatory role of tumor

necrosis factor (TNF)alpha 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 expression of muscle Mfn2 mRNA increased threefold after

reduction in body weight, and a positive correlation between muscle

Mfn2 expression and insulin sensitivity was again detected. In vitro

experiments revealed an inhibitory effect of TNFalpha 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, TNFalpha and interleukin-6 downregulate Mfn2

expression and may participate 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 molecular mechanism

for alterations in mitochondrial function in obesity or type 2

diabetes.