Inhibition of adipose tissue lipolysis increases intramuscular lipid and glycogen use in vivo in humans

Abstract

This study investigates the consequences of inhibition of adipose tissue lipolysis on skeletal muscle substrate use. Ten subjects were studied at rest and during exercise and subsequent recovery under normal, fasting conditions (control trial, CON) and following administration of a nicotinic acid analog (low plasma free fatty acid trial, LFA). Continuous [U- 13 C]palmitate and [6, H2]glucose infusions were applied to quantify plasma free fatty acid (FFA) and glucose oxidation rates and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected to measure 1) fiber type-specific IMTG content; 2) allosteric regulators of hormone-sensitive lipase (HSL), glycogen phosphorylase, and pyruvate dehydrogenase; and 3) the phosphorylation status of HSL at Ser 563 and Ser 565. Administration of a nicotinic acid analog (acipimox) substantially reduced plasma FFA rate of appearance and subsequent plasma FFA concentrations (P Ͻ 0.0001). At rest, this substantially reduced plasma FFA oxidation rates, which was compensated by an increase in the estimated IMTG use (P Ͻ 0.05). During exercise, the progressive increase in FFA rate of appearance, uptake, and oxidation was prevented in the LFA trial and matched by greater IMTG and glycogen use. Differential phosphorylation of HSL or relief of its allosteric inhibition by long-chain fatty acyl-CoA could not explain the increase in muscle TG use, but there was evidence to support the contention that regulation may reside at the level of the glucose-fatty acid cycle. This study confirms the hypothesis that plasma FFA availability regulates both intramuscular lipid and glycogen use in vivo in humans. muscle metabolism; intramyocellular triacylglycerol; fat oxidation; insulin resistance ELEVATED PLASMA FREE FATTY ACID (FFA) concentrations are associated with obesity and the development of insulin resistance (38,44). Combined with the fact that, in obese and/or type 2 diabetes patients, skeletal muscle shows a reduced capacity to oxidize FFA (20), this likely explains the increased intramyocellular triacylglycerol (IMTG) storage in these subjects (15,27,53). In agreement, various studies have reported a strong relationship between elevated plasma FFA levels, IMTG accretion, and insulin resistance (22,32,34). Insights from various lipid infusion studies suggest that elevated plasma FFA delivery and/or impaired fatty acid (FA) oxidation, result in intramyocellular accumulation of triacylglycerol (TG) and FA metabolites (such as fatty acyl-CoA, diacylglycerol, and ceramides), which are likely to induce defects in the insulinsignaling cascade, causing skeletal muscle insulin resistance (1,3,16,42,65).Insulin resistance can subsequently lead to the development of the hyperglycemic and hyperinsulinemic state that is associated with type 2 diabetes and accompanied by major disturbances in skeletal muscle substrate metabolism (17, 37). These disturbances produce a state of metabolic inflexibility that stimulates IMTG storage at the expense of its oxidation (20...

Prolonged Swimming Exercise Does Not Affect Contents and Fatty Acids Composition of Rat Muscle Triacylglycerol

“…In the present study, TG content in the soleus muscle was considerably (3-5 times) higher than those in the other muscles in both experiments. Our results supported the previous findings [8][9][10]13,25) , but the prolonged swimming, even for 4 h, did not reduce the TG contents of the soleus muscle in either experiment at all. In the present study, it is not clear whether or not MTG was utilized as an energy substrate, because the MTG contents were not measured directly.…”

“…As well as these previous old reports, van Loon 10) demonstrated more than 60% net decline in type-I muscle fiber lipid content following 120 min of exercise. It has been well known that red-type muscles contain about three times more lipids than white-type muscles [8][9][10]13,25) . It was also reported that the reduction rate of TG in red muscles during exhaustive exercise was also considerably higher than that in white muscles 8,11,12) , indicating that muscle fat oxidation was noticeably higher in red muscles contained more mitochondria.…”

The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

“…Furthermore, it is plausible that we have underestimated the potential for fatty acids to support muscle energy metabolism (35,36), as we did not specifically enrich the perfusate with free fatty acids in the present study (although intramuscular stores would be plentiful). It would seem, from the higher oxygen consumption and lower glucose and glycogen utilization, that muscle lipid utilization must have been increased to some extent.…”

Effects of Physical Exercise on Inflammatory Markers of Atherosclerosis

“…Infact, exercise training involves multiple metabolic adaptations including increased preexercise skeletal muscle glycogen content, enhanced activity of key enzymes involved in the -oxidation [117], increased sensitivity of adipose tissue to epinephrine-stimulated lipolysis [118], and increased oxidation of intramuscular triglycerides [119], whereby the capacity to oxidize fat is increased [120]. As a consequence, the trained skeletal muscle is less dependent on plasma glucose and muscle glycogen as substrate during exercise [121].…”