METRNL Rescues Glucose Intolerance and Ameliorates Obesity Phenotype in a Diet‐Induced Model of Obesity
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abstract
Physical inactivity is a primary modifiable risk factor for obesity and type 2 diabetes (T2D), metabolic diseases that are rampant in both pediatric/adult populations. Endurance exercise has been shown to prevent/attenuate the onset and progression of obesity/T2D. We postulated that exercise mediated these pro‐metabolic effects on distal fat depots and other organs via secretory myokines. Our lab has identified two such myokines: interleukin‐15 (IL‐15) and meteorin‐like protein METRNL. Here we administered these two myokines, singularly and in combination, to deduce the respective potency in treating obesity by utilizing a diet‐induced model of obesity. C57Bl/6 mice were fed high‐fat diet (HFD; 60% kcal from fat) for 6 months until the animals were hyperglycemic and glucose intolerant. Subsequently the animals were divided into HFD control, endurance exercise (15 m/min for 60 min, 5 days/week, END), or given intravenous injections of recombinant METRNL (0.4 ng/kg/day, 3x/week, MET), IL‐15 (25 ng/kg/day, 3x/week), or a combination group of both IL‐15 and METRNL (COMBO) for 8 weeks. Treatment with METRNL or COMBO normalized serum glucose levels, improved glucose tolerance, and reduced body and fat weight, increased pancreas weight as effectively as the mice in END group (all P < 0.05). Inguinal fat analyses showed a marked improvement in gene networks involved in mitochondrial biogenesis and browning of the fat (increased ucp1, prdm16, and cidea expression), and COX activity in END, MET, and COMBO groups in tandem. IL‐15 treatment alone had no effect on these indices. Our data clearly establishes treatment with METRNL as an effective therapeutic approach to counteract diet‐induced obesity. Funded by NSERC and CIHR.
