Depletion of the APC/C cofactor Cdh1 in mature adipocytes protects against diet-induced obesity

Abstract

The Anaphase Promoting Complex or Cyclosome (APC/C) is an E3 ubiquitin ligase that promotes proteasomal degradation of mitotic cyclins and other cell cycle regulators. During the G1 phase of the cycle its activity is strictly dependent on its cofactor Cdh1. Over the last few years, our group has been addressing the biological function of the APC/C-Cdh1 complex in mammals using mouse models of Cdh1 de ciency, and we have previously established its relevance in several differentiation processes. However, not much is known about the role of this complex in fully differentiated cells or tissues. To get further insight into the function of this ubiquitin ligase in adipose tissues we speci cally depleted Cdh1 in mature adipocytes in mice. These animals displayed smaller visceral white fat depots and were found to be resistant to high fat diet-induced obesity and glucose intolerance. Moreover, signi cantly increased levels of the mitochondrial uncoupling protein UCP1 were detected in all of the Cdh1-depleted fat depots, both white and brown. Consistent with this observation, mutant mice showed an improved thermoregulation capacity upon cold exposure. In addition, acute Cdh1 depletion in in vitro di erentiated adipocytes also led to an important upregulation of the UCP1 protein. However, UCP1 mRNA was not concomitantly upregulated, pointing to protein stabilization as the underlying mechanism for the increased presence of UCP1. In support of this idea, inhibiting the proteasome caused a similar raise in UCP1 levels in wild type but not in Cdh1-de cient adipocytes, possibly indicating that UCP1 could be degraded in a proteasome and Cdh1-dependent way. Together, these results suggest that APC/C-Cdh1 could directly or indirectly control UCP1 protein stability and, as a result, thermal homeostasis and energy expenditure. Furthermore, they raise the possibility that Cdh1 might be a novel anti-obesity factor with therapeutic potential in humans.