Inactivation of UCP1 and the Glycerol Phosphate Cycle Synergistically Increases Energy Expenditure to Resist Diet-induced Obesity

Abstract

Our current paradigm for obesity assumes that reduced thermogenic capacity increases susceptibility to obesity, whereas enhanced thermogenic capacity protects against obesity. Here we report that elimination of two major thermogenic pathways encoded by the mitochondrial uncoupling protein (Ucp1) and mitochondrial glycerol-3-phosphate dehydrogenase (Gdm) result in mice with increased resistance to diet-induced obesity when housed at 28°C, provided prior adaptation occurred at 20°C. Obesity resistant Gdm ؊/؊ ⅐Ucp1 ؊/؊ mice maintained at 28°C have increased energy expenditure, in part through conversion of white to brown adipocytes in inguinal fat. Increased oxygen consumption in inguinal fat cell suspensions and the up-regulation of genes of mitochondrial function and fat metabolism indicated increased thermogenic activity, despite the absence of UCP1, whereas liver and skeletal muscle showed no changes in gene expression. Additionally, comparisons of energy expenditure in UCP1-deficient and wild type mice fed an obesogenic diet indicates that UCP1-based brown fat-based thermogenesis plays no role in so-called diet-induced thermogenesis. Accordingly, a new paradigm for obesity emerges in which the inactivation of major thermogenic pathways force the induction of alternative pathways that increase metabolic inefficiency.Obesity is a disorder of energy homeostasis that results when energy intake exceeds energy expenditure. This simplistic relationship belies the complexity of the behavioral and physiological mechanisms underlying phenotypic variability among humans in both energy intake and energy expenditure (1-3). A homeostatic model has been developed based on neuroendocrine polypeptides, secreted by peripheral tissues, that act on centers in the hypothalamus to reciprocally regulate feeding behavior and energy expenditure. Although it has been proposed that these neuropeptides act simultaneously to regulate energy intake and expenditure, the thermogenic targets in peripheral tissues are largely unknown (4 -6). Indeed, little attention has been given to centrally controlled thermogenic mechanisms that are independent of mitochondrial uncoupling proteins (UCPs), 3 either UCP1, for which there is strong evidence for a role in rodent models of obesity (7), or the UCP homologues that continue to be proposed for mitochondrial uncoupling functions with little supporting evidence (8, 9). Given the paucity of evidence for UCP1 activity in adult tissues, there is a pressing need to identify novel mechanisms for activating thermogenesis that can be applied to the obesity problem.The uncoupling of mitochondrial substrate oxidation from ATP synthesis by UCP1 in brown adipose tissue is widely recognized for its role in maintaining a normal body temperature during exposure to cold (10 -13). There is also strong evidence that inducing UCP1-based thermogenesis through pharmacological or genetic manipulation reduces excessive adiposity (14). However, these experimentally induced phenotypes may not be indicative of a normal physio...

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…A large body of literature links increased dietary fat intake with obesity and cancer progression [59], but it is becoming clear that factors affecting obesity are altered at ST. For example, a UCP-1 knockout mouse model showed deficits in coldinduced non-shivering thermogenesis as expected, but failed to develop the expected obesity phenotype [60,61]. Several groups have now shown that this unexpected lack of the predicted phenotype was because the mice were housed at ST, and when these mice are housed at TT (and are not burning energy through adaptive thermogenesis) they do become obese [61][62][63][64]. This effect of ST on obesity has been observed in other models as well [65][66][67], and it is clear that precise data on the linkage between diet, obesity, and cancer should be re-examined in the context of absence of cold stress.…”

Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion

“…One reason for its limited expression is the energy loss resulting from the conversion of NADH to FADH 2 ; this energy is converted into heat [64]. The energy loss has been suggested to allow this shuttle to transfer electrons against an unfavourable electron gradient, i.e.…”

“…In contrast, activity in the malate-aspartate shuttle does not result in any loss of energy. In brown adipose tissue, a high rate of fuel oxidation is required to generate heat [64]. Likewise, in the β-cell, the glycerol phosphate shuttle allows a high glycolytic rate even in situations when the mitochondrial redox potential is very high; this would extend the range of glucose concentrations at which insulin can be concentration-dependently secreted.…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…However, it was also demonstrated that a lean phenotype could be induced in mice by augmenting energy expenditure in white adipocytes in the absence of UCP1, by (1) mitochondrial uncoupling elicited by increased intracellular levels of free fatty acids (Maassen et al 2007;Yehuda-Shnaidman et al 2010), (2) futile cycling between fatty acid synthesis and re-esterification (Ribet et al 2010), or (3) other mechanisms (Granneman et al 2003;Ukropec et al 2006;Anunciado-Koza et al 2008). In this respect, 15-deoxy-delta 12,15-prostaglandin J2, an anti-inflammatory mediator and potent endogenous PPARc agonist (Forman et al 1995;Kliewer et al 1995), that is, endogenous analog of TZD was synergistically induced in response to the combination treatment using n-3 polyunsaturated fatty acids and calorie restriction in association with stimulation of mitochondrial biogenesis and fatty acid oxidation in WAT in the absence of UCP1 (Flachs et al 2011).…”