Abdominal Adiposity and Muscle Mitochondrial Functions

Numerous studies have demonstrated that excess perivisceral adipose tissue is associated with metabolic diseases such as insulin resistance.

In skeletal muscle, insulin resistance has been correlated with reduced mitochondrial oxidative functions. According to the actual theory, mitochondrial dysfunctions are proposed to play a causal role in the aetiology of insulin resistance. Mechanisms involve increased intramyocellular lipids storage. Yet, the causes responsible for the decline in muscle mitochondrial functions remain to be elucidated.

The investigators hypothesize that these alterations are induced by combined changes in plasma profiles of lipids and adipokines, which originate from perivisceral adipose tissue. The study aims at answering the following questions :

* Are muscle mitochondrial functions altered in association with increased perivisceral adipose tissue storage?
* Do changes in the pattern of plasma lipids and adipokines explain this correlation?

Sixty 35 to 50-years old sedentary men will be included based on their abdominal circumference (from 75 to over 102 cm).

Body composition will be evaluated using dual-energy X-ray absorptiometry and perivisceral, intramuscular and intrahepatic adiposity will be assess by MRI and proton-NMR spectroscopy. Subjects will be also characterized by their glucose tolerance (OGTT), basal metabolism (indirect calorimetry) and maximal oxygen consumption (maximal aerobic power test on exercise bike).

Blood samples will be collected in the fasted state to assess lipids and adipokines concentrations.

Biopsies will be obtained from the vastus lateralis muscle to examine mitochondrial functions (respiration rates, ATP and superoxide anion production rates, maximal activity of oxidative enzyme). Gene expression of key enzymes, protein and transcription factors involved in lipid and energy metabolism will be assessed using real-time quantitative PCR.

Finally, whole body and muscle protein metabolism will be investigated in half of the subjects using tracer infusion (incorporation of L-\[1-13C\]leucine) and biopsies from vastus lateralis, both in the post-absorptive and post-prandial states (test meal)

Eligibility Criteria:
Inclusion Criteria:

* Male subjects
* Age between 35 and 50
* waist circumference \> 75 cm
* Baecke score \< 1 (activity score for sedentary subjects)
* Subjects giving written informed consent
* Subjects willing to comply with the study procedures
* Subjects considered as normal after clinical examination and medical questionnaire

Exclusion Criteria:

* Weight change \> 3 kg within 3 months prior to study
* Patients with type 1 or type 2 diabetes
* Serologic evidence of active hepatitis B or HIV
* History of cancer or significant intestinal, hepatic, renal or cardiovascular disorders within the past 5 years
* History of systemic infections or inflammatory diseases within the past 2 months
* Hypocaloric or special diets (e.g. vegetarian)
* Patients currently known to abuse or to be dependent on any drug, including alcohol (daily consumption \> 20g) and tobacco (daily consumption \> 5 cigarettes)
* CRP \< 5 mg/L
* Blood coagulation disorders
* Allergy to xylocaïne
* for test meal : Food allergy (particularly milk allergy and lactose intolerance)
* for MRI : Claustrophobia