Mitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the develop-

Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation. The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency—especially in obesity and associated metabolic disorders—and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances. This study focuses on the importance of diet, gut microbiota, and liver metabolism in determining glycine availability in obesity and associated metabolic disorders.

Chronic bilateral subthalamic stimulation leads to a spectacular clinical improvement in patients with motor complications. However, the post-operative body weight gain involved may limit the benefits of surgery and induce critical metabolic disorders. Twenty-four Parkinsonians (61.1 +/- 1.4 years) were examined 1 month before (M - 1) and 3 months after (M + 3) surgery. Body composition and energy expenditure (EE) were measured (1) over 36 h in calorimetric chambers (CC) with rigorous control of food intakes and activities [sleep metabolic rate, resting activities, meals, 3 or 4 sessions of 20 min on a training bicycle at 13 km/h and daily EE] and (2) in resting conditions (basal metabolic rate) during an acute L-dopa challenge (M - 1) or according to acute 'off' and 'on' stimulation (M + 3). Before surgery, EE was compared between the Parkinsonian patients and healthy subjects matched for height and body composition (metabolic rate during sleep, daily EE) or matched to predicted values (basal metabolic rate). Before surgery, in Parkinsonian men but not women, (1) daily EE was higher while sleep metabolic rate was lower compared to healthy matched men (+9.2 +/- 3.9 and -8.2 +/- 2.3%, respectively, P < 0.05) and (2) basal metabolic rate (L-dopa 'on') was higher than predicted basal metabolic rate (+11.5 +/- 4.0%, P < 0.05) but was further increased without L-dopa (+8.4 +/- 3.2% vs L-dopa 'on', P < 0.05). EE during daily activities was higher during 'off' periods compared to 'on' periods for both men (+19.3 +/- 3.3%, P < 0.0001) and women (+16.1 +/- 4.7%, P < 0.01). After surgery, there was a 3.4 +/- 0.6 kg (P < 0.0001) body weight increase together with fat mass (P < 0.0001) and fat-free mass (P < 0.05) in Parkinsonian men and a 2.6 +/- 0.8 kg (P < 0.05) body weight increase together with fat mass (P < 0.05) in Parkinsonian women. Sleep metabolic rate increased in men (+7.5 +/- 2.0%, P < 0.01) to reach control values but remained unchanged in women. Daily EE decreased significantly in both men and women (-7.3 +/- 2.2% and -13.1 +/- 1.7%, respectively, P < 0.01) but there was no correlation between daily EE changes and body weight gain. Parkinson's disease is associated with profound alterations in the central control of energy metabolism. Normalization of energy metabolism after DBS-STN implantation may favour body weight gain, of which quality was gender specific. As men gained primarily fat-free mass, a reasonable weight gain may be tolerated, in contrast with women who gained only fat. Other factors such as changes in free-living physical activity may help to limit body weight gain in some patients.

. Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise. Am J Physiol Endocrinol Metab 287: E513-E522, 2004. First published May 18, 2004 10.1152/ ajpendo.00334.2003.-Regular aerobic exercise strongly influences muscle metabolism in elderly and young; however, the acute effects of aerobic exercise on protein metabolism are not fully understood. We investigated the effect of a single bout of moderate walking (45 min at ϳ40% of peak O 2 consumption) on postexercise (POST-EX) muscle metabolism and synthesis of plasma proteins [albumin (ALB) and fibrinogen (FIB)] in untrained older (n ϭ 6) and younger (n ϭ 6) men. We measured muscle phenylalanine (Phe) kinetics before (REST) and POST-EX (10, 60, and 180 min) using L-[ring-2 H5]phenylalanine infusion, femoral arteriovenous blood samples, and muscle biopsies. All data are presented as the difference from REST (at 10, 60, and 180 min POST-EX). Mixed muscle fractional synthesis rate (FSR) increased significantly at 10 min POST-EX in both the younger (0.0363%/h) and older men (0.0830%/h), with the younger men staying elevated through 60 min POST-EX (0.0253%/ h). ALB FSR increased at 10 min POST-EX in the younger men only (2.30%/day), whereas FIB FSR was elevated in both groups through 180 min POST-EX (younger men ϭ 4.149, older men ϭ 4.107%/ day). Muscle protein turnover was also increased, with increases in synthesis and breakdown in younger and older men. Phe rate of disappearance (synthesis) was increased in both groups at 10 min POST-EX and remained elevated through 60 min POST-EX in the older men. A bout of moderate-intensity aerobic exercise induces short-term increases in muscle and plasma protein synthesis in both younger and older men. Aging per se does not diminish the protein metabolic capacity of the elderly to respond to acute aerobic exercise. muscle protein synthesis; moderate walking; plasma proteins THE NORMAL AGING PROCESS in healthy humans is often accompanied by an involuntary decade-by-decade loss of physical capability. The inability to maintain physical function with advanced age is largely attributable to several key factors, including inadequate nutrition (10, 45), hormonal alterations (8,22,47,49), reduced mitochondrial protein synthesis (2, 50), DNA alterations (43, 50), and physical inactivity (23, 38). Not unlike frail elderly, healthy elderly often display greater adiposity and lower fat-free mass than their younger counterparts. The mechanism(s) behind the apparent imbalance between protein synthesis and breakdown with aging has not been fully elucidated and remains the subject of much debate (53,54,62). Regardless of whether elderly do or do not have diminished whole body or muscle protein metabolism, the more important issue remains whether an intervention such as exercise can positively influence protein metabolism.Considerable effort has been directed at studying the metabolic consequences and physiological significance of both acute and repeated bouts of aerobic and resistance exercise....

Aging is associated with a redistribution of both fat and lean tissue within the body. Intra-abdominal fat (IAF) accumulates more rapidly than total fat while the loss of lean body mass is mostly due to sarcopenia. Increase of visceral fat plays a major role in the pathogenesis of insulin resistance, which leads to type II diabetes and also to cardiovascular diseases. This review is focussed on the relationships that exist between the accumulation of IAF and insulin resistance during aging. The various methods available for assessing IAF are briefly reviewed; imaging techniques are the only reference methods, and their availability is limited. Insulin resistance that appears with aging is caused by accumulation of IAF, rather than by aging per se. Studies done in type II diabetic patients suggest that the metabolic link between increased IAF and insulin resistance could well be the increased availability and/or oxidation of free fatty acids. Physical inactivity certainly enhances both IAF accumulation and, more directly, insulin resistance. Independent and significant effects of menopause or of sarcopenia on insulin resistance remain to be established. The influence of hormonal changes, reduced fatty acid utilization, and resistance to leptin on IAF accumulation are also discussed. Although it is difficult to determine the independent influence of each of these factors, IAF accumulation seems to be a central and important determinant of cardiovascular risk. The last part of this review is devoted to protein metabolism and focused on the preservation of protein metabolism in the liver during aging.

We characterize the coordinated and time-dependent processes that occur in human adipose tissue during the early phase of weight gain in healthy subjects and identify pathways representing potential targets in pathologies of adipose development, including obesity.

The study aimed at determining whether aging and/or sedentariness impairs muscle fat oxidative capacity (OXFA) and whether this was associated with increased risk to develop insulin resistance. We first examined muscle mitochondrial functions, OXFA and insulin sensitivity (ISI; evaluated during an oral glucose tolerance test) in a cross-sectional study with 32 sedentary (S) and endurance-trained (T), young (Y) and elderly (E) men (24.2+/-2.6 vs. 66.6+/-3.2 yr). As for mitochondrial functions, OXFA was higher in T than in S but similar between age groups (SY 41.8+/-11.3, TY 68.0+/-17.7, SE 40.1+/-14.1, TE 73.1+/-20.1 palmitate x min(-1) x g wet tissue(-1); activity P<0.0001, age P=NS, activity x age P=NS). Similar results were obtained with ISI (SY 6.2+/-2.2, TY 11.4+/-4.4, SE 5.9+/-1.5, TE 11.0+/-3.5, activity P<0.001, age P=NS, activity x age P=NS). Stepwise regression showed that, among body composition, VO2max and muscle biochemical characteristics, OXFA was the main predictor of ISI (r=0.60, P<0.001). We subsequently showed in eight sedentary elderly subjects (63.5+/-3.3 yr) that OXFA and insulin sensitivity (measured using insulin clamp) improved in parallel after 8 weeks of endurance training (r=0.79, P<0.01). We concluded that mitochondrial functions, OXFA and ISI, are not impaired by age but by physical inactivity and are closely correlated.

Fenofibrate treatment started within 1 week postburn and continued for 2 weeks significantly decreased plasma glucose concentrations by improving insulin sensitivity, insulin signaling, and mitochondrial glucose oxidation. Fenofibrate may be a potential new therapeutic option for treating insulin resistance following severe burn injury.