Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

Abstract

Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:(i) the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport), (ii) the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently (iii) the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes).This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.

Clinical significance of adaptive thermogenesis

“…7,49 It is, however, not the aim of this paper to cover extensively EE regulatory systems, and readers can refer to several papers that have been written on the topic. 5,42,[48][49][50][51][52][53][54][55] Similarly, cellular mechanisms on the basis of human body thermogenesis, such as mitochondrial adenosine triphosphate synthesis efficiency, 56,57 uncoupling proteins 53,58 and their related increased muscle efficiency 59 will not be covered in this paper, as they have been directly addressed in their respective cited references. This conceptual paper will rather describe three conditions that have been associated to adaptive thermogenesis and that may thus represent limiting factors in weight loss, and confer a significant susceptibility to weight gain/regain in some individuals: body weight loss and regain cycles, organochlorine plasma concentration and hypoxia in severe form of obstructive sleep apnea.…”

The thrifty ‘catch-up fat’ phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome

“…urocortins). 93,94,98 These hormones can interact to stimulate thermogenesis via the enhancement of AMPK and PI3K signaling either by acting directly on skeletal muscle, or centrally through the sympathetic-thyroid axis via norepinephrine (NE) and triiodothyronine (T3). By interfering with PI3K and/or AMPK signaling in skeletal muscle, the actions of the adipose-specific signal(s) that sense the state of depletion (or delayed expansion) of the adipose tissue fat stores will suppress skeletal muscle thermogenesis, which during refeeding will lead to concomitant insulin and leptin resistance.…”

Ezetimibe-associated myopathy in monotherapy and in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

“…They concluded that because this reaction occurred with ezetimibe monotherapy and was accompanied with other signs of impaired fatty acid oxidation, the toxicity may not be related to a pharmacokinetic interaction but to impaired fatty acids oxidation. Indeed, the concept of lipotoxicity is of importance and is evolving in the literature (17).…”