1180-P: Short-Term Low-Protein Diet Ameliorates Metabolic Dysfunction in Diabetic Lipodystrophic Mice

Abstract

Long-term ad libitum dietary restriction such as low-protein diet (LPD) improves metabolic health and extend the life spans of mice and possibly human. However, most studies conducted thus far have mainly focused on preventive rather than the treatment potential of LP diets. To determine whether dietary protein or caloric restriction could be used to treat preexisting metabolic symptoms, particularly in a more severely affected mouse model, we subjected hyperglycemic lipodystrophic IRFKO (adipose-specific insulin receptor knockout) mice to LPD (5.1% kcal from protein). Interestingly, postprandial blood glucose (BG) values of the IRFKO mice began to improve 10 days after the introduction of LPD. The IRFKO mice became normoglycemic 2 weeks after the onset of the LPD treatment. Activation of adaptive thermogenesis in brown (BAT) and beige adipose tissues promotes energy expenditure (EE) and utilization of BG and triglyceride (TG). A LPD has been previously shown to promote EE via the sympathetic nervous system (SNS). Consistent with previous study, we observed that a LPD acutely and sustainably upregulates EE in both the WT and IRFKO mice. This is likely due to LPD dramatically improves BAT functions by transforming the whitened unilocular lipid droplet BAT in the IRFKO mice into normal looking brown multi-locular lipid droplet BAT within 1 week of LPD treatment. This is further supported by significant increase in thermogenic markers expression in the BAT after LPD. Besides thermogenic markers, we also observed a time-dependent regulation of gene markers for fatty acid transport, oxidation and glucose metabolism in BAT after LPD. Together with changes in blood chemistry in the IRFKO mice, we think that glucose and lipid-lowering effects of LPD is the consequence of continuous activation of EE leading to utilization and depletion of systemic thermogenic fuels. Taken together, our data suggest that short-term LPD could be a potential strategy for the treatment of metabolic syndrome. Disclosure M. D. Munoz: None. M. A. Mccann: None. P. Kim: None. C. Liew: None.