Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

Abstract

Dubé JJ, Coen PM, DiStefano G, Chacon AC, Helbling NL, Desimone ME, Stafanovic-Racic M, Hames KC, Despines AA, Toledo FG, Goodpaster BH. Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance. Am J Physiol Endocrinol Metab 307: E1117-E1124, 2014. First published October 28, 2014; doi:10.1152/ajpendo.00257.2014.-We hypothesized that acute lipid-induced insulin resistance would be attenuated in highoxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload. lipids; mitochondria; skeletal muscle CHRONIC SUBSTRATE OVERLOAD, coupled with physical inactivity, is a key mediator of the development of obesity and insulin resistance (49). It has been suggested that mitochondrial dysfunction (1, 17), perhaps a result of nutrient oversupply, particularly saturated fatty acids and/or physical inactivity, plays a key role in decreased insulin action observed in the obese state. However, there is evidence to suggest that mitochondrial content and performance are normal in insulinresistant obese subjects (14). Although there is controversy regarding the influence of mitochondrial performance on the development of insulin resistance (17,22), there is little debate that increased physical activity (i.e., aerobic exercise) provides a necessary stimulus for increased mitochondrial content (24), capacity for fat oxidation (6), and improved insulin sensitivity (13). Yet few studies have directly assessed the effects of lipid oversupply on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance in high-vs. lowoxidative muscle (9, 40).Using the exogenous lipid infusion model of insulin resistance (7, 26), we hypothesized that excess fatty acids would be preferentially oxidized in enduranc...

Metabolic Flexibility in Health and Disease

“…Similarly, lipid overload, often used as a model for insulin resistance (Brehm et al, 2006; Itani, 2002; Yu, 2002), may represent a model of metabolic flexibility rather than revealing a pathological mechanism of insulin resistance. In support of this, Phelix et al and Dube et al demonstrated in independent studies (Dube et al, 2014; Phielix et al, 2012) that endurance-trained athletes who have a high oxidative capacity in muscle can increase fatty acid oxidation in response to lipid overload, but they preserve glycogen storage within muscle at the expense of decreasing glucose oxidation (Figure 1, data obtained from ( Dube et al, 2014)). This enhanced metabolic flexibility was associated with a higher mitochondrial capacity in exercise-trained muscle (Dube et al, 2014; Phielix et al, 2012).…”

“…In support of this, Phelix et al and Dube et al demonstrated in independent studies (Dube et al, 2014; Phielix et al, 2012) that endurance-trained athletes who have a high oxidative capacity in muscle can increase fatty acid oxidation in response to lipid overload, but they preserve glycogen storage within muscle at the expense of decreasing glucose oxidation (Figure 1, data obtained from ( Dube et al, 2014)). This enhanced metabolic flexibility was associated with a higher mitochondrial capacity in exercise-trained muscle (Dube et al, 2014; Phielix et al, 2012). Recent evidence also suggests that circadian variation in the molecular metabolic machinery can influence metabolic flexibility (Bass and Lazar, 2016).…”

Muscle Characteristics and Substrate Energetics in Lifelong Endurance Athletes

“…With respect to mitochondria, it has been reported that mitochondrial respiration (21), mitochondrial biogenesis (32), and perhaps oxidative capacity and energy production decline with aging. However, it's generally accepted that aerobic exercise training, in both older (9) and younger (11) previously sedentary subjects, results in enhanced mitochondrial oxidative capacity. In agreement with data from Proctor et al (39), we did not observe any differences in mitochondrial capacity between the cohorts in this study.…”

Using Isolated Mitochondria from Minimal Quantities of Mouse Skeletal Muscle for High throughput Microplate Respiratory Measurements

“…Importantly, skeletal muscle mitochondria play a specific role in exercise capacity 2 , aging 3 , degenerative disease 4 and Type II diabetes 5 . As an aging society, and Type II Diabetes being the 7 th leading cause of death in the United States 6 , the need for methods that assess mitochondrial function has become increasingly more prevalent in biomedical research 7,8 .…”