Editors' ChoiceMetabolism

Fat chance for creatine deficiency

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Science Translational Medicine  13 Sep 2017:
Vol. 9, Issue 407, eaap9292
DOI: 10.1126/scitranslmed.aap9292

Abstract

Creatine metabolism in adipose tissue is necessary to burn off extra dietary calories and helps prevent obesity.

Although it may be amusing to think we naturally burn off extra calories, our bodies in fact—to an extent—do just that. The body is thought to regulate its weight such that an increase in caloric intake is met with increased energy expenditure in the form of heat. (The reverse is also true: a long-term decrease in food intake leads to reduced energy expenditure, making it harder to keep weight off.) Spiegelman and colleagues show that creatine metabolism in adipocytes is necessary for this diet-induced thermogenesis.

To examine the physiological effects of creatine on fat metabolism, the authors created knockout mice lacking the rate-limiting enzyme of its biosynthesis, glycine amidinotransferase (GATM), specifically in adipocytes. As GATM is active in other tissues, its selective inhibition in fat cells prevents confounding physiological effects. Loss of GATM resulted in lowered levels of creatine and related intermediate compounds in brown fat, a tissue where thermogenesis is known to take place. The knockout mice exhibited lowered glucose tolerance and substantial adipose accumulation. They also had a lowered basal metabolic rate upon high-fat feeding compared with controls, as inferred by resting oxygen consumption, suggesting the obesity in knockout mice is driven by impaired diet-induced thermogenesis. In line with this inference, Gatm mRNA expression increased upon high-fat feeding in wild-type controls only. The metabolic defect was rescued by dietary creatine supplementation, confirming the involvement of the biochemical pathway in thermogenesis. The heat-generating effect of creatine likely occurs by its stimulation of mitochondrial ATP turnover, as previously shown by the group.

Although restricted to mice, the study provides an important key to understanding metabolic factors that stabilize against weight gain. Whether increasing creatine metabolism in a nonknockout background can further promote calorie-shedding thermogenesis is currently unknown. As individuals who are predisposed to obesity tend to have lowered metabolic capacity to lose calories as heat, it should prove interesting to see if the pathway can be targeted in humans.

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