Peroxisome proliferator‐activated receptor δ controls muscle development and oxydative capability

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors exerting several functions in development and metabolism. The physiological functions of PPARdelta remain elusive. By using a CRE-Lox recombination approach, we generated an animal model for muscle-specific PPARdelta overexpression to investigate the role of PPARdelta in this tissue. Muscle-specific PPARdelta overexpression results in a profound change in fiber composition due to hyperplasia and/or shift to more oxidative fiber and, as a consequence, leads to the increase of both enzymatic activities and genes implicated in oxidative metabolism. These changes in muscle are accompanied by a reduction of body fat mass, mainly due to a large reduction of adipose cell size. Furthermore, we demonstrate that endurance exercise promotes an accumulation of PPARdelta protein in muscle of wild-type animals. Collectively, these results suggest that PPARdelta plays an important role in muscle development and adaptive response to environmental changes, such as training exercise. They strongly support the idea that activation of PPARdelta could be beneficial in prevention of metabolic disorders, such as obesity or type 2 diabetes.

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

“…In recent years PPARδ has emerged as a key protein in the regulation of energy metabolism by its ability to enhance fatty acid catabolism, energy uncoupling and insulin sensitivity in the liver, adipose tissue and skeletal muscle [6][7][8][9][10]36].…”

“…PPARδ acts as a regulator of fatty acid β-oxidation in both adipose tissue and skeletal muscle. In skeletal muscle, overexpression of Ppard in mice increases oxidative metabolism, changes muscle fibre type towards oxidative type I fibres and improves physical endurance thereby averting obesity induced by a high-fat diet or genetically [6,7]. Additionally, a recent study of genetically modified mice provides evidence that PPARδ regulates glucose metabolism and insulin sensitivity in both skeletal muscle and the liver, interestingly indicating a subtle PPARδ-controlled change in substrate utilisation [8].…”

Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids

“…As the impairment of glucose utilisation prevails independently of the muscle fibre type examined (i.e. in both red and white muscle), it is unlikely to depend on PPAR-δ-induced fibre type conversion which has been suggested to occur in mice subjected to overexpression of PPAR-δ in skeletal muscle [9,11]. Furthermore, the finding that the PPAR-α agonist WY14643 likewise inhibits glucose utilisation in isolated muscle, but to a quantitatively much smaller extent than GW501516, corroborates previous evidence that these two PPAR subtypes transduce similar effects, but that PPAR-δ is of predominant importance in native skeletal muscle of rodents [5,10].…”

“…The notion that such impairment will derange whole-body glucose homeostasis relates to studies in which increased fatty acid utilisation was triggered by the mass effect of elevated ambient lipid concentrations [20][21][22]. This clearly differs from the fuel switch induced by PPAR-δ, which occurs together with elevated glucose consumption and fatty acid synthesis in the liver [25] as well as with an increased capacity of the mitochondrial apparatus in skeletal muscle, which is therefore capable of oxidising larger amounts of lipid [5,9,11]. It is of note that these changes contrast with the fundamental derangement of insulin-resistant skeletal muscle, which is characterised by a distinctly reduced oxidative capacity and a pronounced preference for glucose over fatty acids as the oxidative substrate [26][27][28].…”

“…In this context, the quantitatively most important target organ seems to be skeletal muscle, which makes a major contribution to whole-body fuel oxidation and expresses PPAR-δ more abundantly than other PPAR subtypes [10]. Accordingly, targeted overexpression of PPAR-δ in mouse skeletal muscle distinctly elevates the number of red type-1-like fibres, characterised by high mitochondrial density and oxidative capacity [9,11]. Furthermore, several studies have consistently shown that agonists of PPAR-δ markedly increase the rate of fatty acid oxidation by specimens of skeletal muscle both ex vivo and in vitro [4,5,10].…”