High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H(2)O(2) emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H(2)O(2) emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

Dohm GL, Cortright RN, Lust RM. Artificial selection for high-capacity endurance running is protective against high-fat diet-induced insulin resistance. Am J Physiol Endocrinol Metab 293: E31-E41, 2007. First published March 6, 2007; doi:10.1152/ajpendo.00500.2006.-Elevated oxidative capacity, such as occurs via endurance exercise training, is believed to protect against the development of obesity and diabetes. Rats bred both for low (LCR)-and high (HCR)-capacity endurance running provide a genetic model with inherent differences in aerobic capacity that allows for the testing of this supposition without the confounding effects of a training stimulus. The purpose of this investigation was to determine the effects of a high-fat diet (HFD) on weight gain patterns, insulin sensitivity, and fatty acid oxidative capacity in LCR and HCR male rats in the untrained state. Results indicate chow-fed LCR rats were heavier, hypertriglyceridemic, less insulin sensitive, and had lower skeletal muscle oxidative capacity compared with HCR rats. Upon exposure to an HFD, LCR rats gained more weight and fat mass, and their insulin resistant condition was exacerbated, despite consuming similar amounts of metabolizable energy as chow-fed controls. These metabolic variables remained unaltered in HCR rats. The HFD increased skeletal muscle oxidative capacity similarly in both strains, whereas hepatic oxidative capacity was diminished only in LCR rats. These results suggest that LCR rats are predisposed to obesity and that expansion of skeletal muscle oxidative capacity does not prevent excess weight gain or the exacerbation of insulin resistance on an HFD. Elevated basal skeletal muscle oxidative capacity and the ability to preserve liver oxidative capacity may protect HCR rats from HFD-induced obesity and insulin resistance. fatty acid; lipid metabolism; liver; heart; skeletal muscle THE INCIDENCE OF METABOLIC DISEASES such as obesity and type II diabetes is increasing dramatically and is strongly linked to the rise in cardiovascular disease. In 2002, ϳ64% of the population in the United States was classified as overweight or obese (22), and health care costs attributable to these conditions exceeded $78 billion dollars (13). Although type II diabetes afflicts a substantially lower percentage (ϳ6.3%) of the population (9), this disease accounts for $132 billion in annual health care costs (24). With the increase in the incidence of such metabolic diseases reaching epidemic proportions and the threat of health care costs spiraling out of control, much research has been focused toward elucidating the mechanisms involved in the etiology of these conditions in hopes of ultimately discovering better treatments. Several therapies are currently used to alleviate symptoms of these diseases, but other than dietary modifications, endurance exercise is the only universally prescribed treatment.Enhanced aerobic capacity has long been associated with diminished morbidity and improvements in functional living, yet all the physiological mechanisms ...

Metformin is a widely prescribed drug for treatment of type 2 diabetes, although no cellular mechanism of action has been established. To determine whether in vivo metformin treatment alters mitochondrial function in skeletal muscle, respiratory O 2 flux and H 2 O 2 emission were measured in saponin-permeabilized myofibers from lean and obese (fa/fa) Zucker rats treated for 4 wks with metformin. Succinate-and palmitoyl-carnitine-supported respiration generated >2-fold higher rates of H 2 O 2 emission in myofibers from untreated obese versus lean rats, indicative of an obesity-associated increased mitochondrial oxidant emitting potential. In conjunction with improved glycemic control, metformin treatment reduced H 2 O 2 emission in muscle from obese rats to rates near or below those observed in lean rats during both succinate-and palmitoylcarnitine-supported respiration. Surprisingly, metformin treatment did not affect basal or maximal rates of O 2 consumption in muscle from obese or lean rats. Ex vivo dose-response experiments revealed that metformin inhibits complex I-linked H 2 O 2 emission at a concentration ∼2 orders of magnitude lower than that required to inhibit respiratory O 2 flux. These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H 2 O 2 emission by blocking reverse electron flow without affecting forward electron flow or respiratory O 2 flux in skeletal muscle.

Noland RC, Woodlief TL, Whitfield BR, Manning SM, Evans JR, Dudek RW, Lust RM, Cortright RN. Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance. Am J Physiol Endocrinol Metab 293: E986-E1001, 2007. First published July 17, 2007; doi:10.1152/ajpendo.00399.2006.-Peroxisomal oxidation yields metabolites that are more efficiently utilized by mitochondria. This is of potential clinical importance because reduced fatty acid oxidation is suspected to promote excess lipid accumulation in obesity-associated insulin resistance. Our purpose was to assess peroxisomal contributions to mitochondrial oxidation in mixed gastrocnemius (MG), liver, and left ventricle (LV) homogenates from lean and fatty (fa/fa) Zucker rats. Results indicate that complete mitochondrial oxidation (CO2 production) using various lipid substrates was increased approximately twofold in MG, unaltered in LV, and diminished ϳ50% in liver of fa/fa rats. In isolated mitochondria, malonyl-CoA inhibited CO2 production from palmitate 78%, whereas adding isolated peroxisomes reduced inhibition to 21%. These data demonstrate that peroxisomal products may enter mitochondria independently of CPT I, thus providing a route to maintain lipid disposal under conditions where malonyl-CoA levels are elevated, such as in insulin-resistant tissues. Peroxisomal metabolism of lignoceric acid in fa/fa rats was elevated in both liver and MG (LV unaltered), but peroxisomal product distribution varied. A threefold elevation in incomplete oxidation was solely responsible for increased hepatic peroxisomal oxidation (CO 2 unaltered). Alternatively, only CO2 was detected in MG, indicating that peroxisomal products were exclusively partitioned to mitochondria for complete lipid disposal. These data suggest tissue-specific destinations for peroxisome-derived products and emphasize a potential role for peroxisomes in skeletal muscle lipid metabolism in the obese, insulin-resistant state. fatty acid; lipid metabolism; liver; heart; skeletal muscle; Zucker rat EXCESS LIPID ACCUMULATION is implicated in the pathophysiology of obesity-associated insulin resistance, and many believe this is secondary to impairments in lipid disposal pathways (22,38,48,52,55,56). Consequently, much research has focused on primary aspects involved in lipid metabolism, such as mitochondrial oxidative capacity, lipid transport, and lipid trafficking. However, an important factor that has largely been overlooked with respect to maintaining a healthy cellular lipid environment is the peroxisome. Peroxisomes are ubiquitously expressed and have a wide range of cellular functions, including a primary role in fatty acid oxidation (68). Unlike mitochondria, peroxisomal ␤-oxidation is incomplete and cannot chain-shorten fatty acids beyond six carbon residues (50), thus leaving a medium-chain acyl-CoA derivative as well as acetylCoA residues. Since peroxisomes lack a tricarboxylic acid cycle and electron transport system, the products of peroxisomal oxidation are not linked di...

ObjectiveRoux-en-Y gastric bypass(RYGB) can cause profound weight loss and improve overall cardiometabolic risk factors. Exercise (EX) training following RYGB can provide additional improvements in insulin sensitivity(SI) and cardiorespiratory fitness. However, it remains unknown if a specific amount of EX post-RYGB is required to achieve additional benefits.MethodsWe performed a post-hoc analysis of participants who were randomized into either a 6-month structured EX program or a health education control (CON). EX(N=56) were divided into tertiles according to the amount of weekly exercise performed, compared to CON(N=42): Low-EX=54±8; Middle-EX=129±4; High-EX=286±40 minutes per week.ResultsThe High-EX lost a significantly greater amount of body weight, total fat mass and abdominal deep subcutaneous abdominal fat compared to CON(p<0.005). SI improved to a greater extent in both the Middle-EX and High-EX compared to CON(p<0.04). Physical fitness (VO2max) significantly improved in the High-EX(+9.3±4.2%) compared to CON(−6.0±2.4%)(p< 0.001). Skeletal muscle mitochondrial state 4(p<0.002) and 3(p<0.04) respiration was significantly higher in the High-EX compared to CON.ConclusionA modest volume of structured exercise provides additional improvements in insulin sensitivity following RYGB, but higher volumes of exercise are required to induce additional weight loss, changes in body composition and improvements in cardiorespiratory fitness and skeletal muscle mitochondrial capacity.