Long-term ad libitum dietary restriction such as low-protein diet (LPD) improves metabolic health and extends the life span of mice and possibly humans. However, most studies conducted thus far have focused on the preventive, but not therapeutic, potential of LPDs. Previously we shown that LPD (5.1% kcal from protein) was able to improve postprandial blood glucose values of the lipodystrophic IRFKO (adipose-specific insulin receptor knockout) mice after 14 days with strong activation of interscapular brown adipose tissue (iBAT) and increase energy expenditure. To determine whether iBAT activation was responsible for the hyperglycemia normalization after the LPD treatment, we surgically denervated iBAT of IRFKO mice before LPD treatment. Blood glucose were measured twice a week for up to 4 weeks, at the end of the monitoring mice were subjected to indirect calorimetry assessment (Promethion, Sable Systems) . Our data showed that surgical denervation of iBAT abolished the hyperglycemia normalization effect of LPD in the IRFKO mice. Morphologically, surgical denervation also prevented the ‘browning’ effect of LPD on the whitening iBAT observed in IRFKO mice. In line with the morphological data, LPD failed to induce thermogenic markers including UCP1 and BMP8b in denervated iBAT. In contrast, iBAT denervation has lesser effects on the LPD-induced energy expenditure and circulating FGF21 level, possibly due to compensation by beige fat formation in the inguinal WAT. Together, our data confirms that hyperglycemia normalization caused by LPD on IRFKO is iBAT activation dependent. Our observation suggests that blood glucose could be utilized to fuel LPD-induced iBAT activation as a mechanism for amino acid homeostasis. Further experimentation needs to be done in order to narrow down the mechanism driving this phenomenon. Taken together, our data suggest that short-term LPD could be a potential strategy for the treatment of metabolic syndrome.


M.D.Munoz: None. A.Zamudio: None. M.A.Mccann: None. C.Liew: None.


NIH RDK109015A1

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