LRP1 Regulates Adiposity by Controlling Energy Balance in MC4R Neurons

Abstract

Hypothalamic low-density lipoprotein receptor-related protein 1 (LRP1), a member of LDL receptor family, plays a pivotal role in the regulation of food intake and body-weight homeostasis. However, the role of LRP1 in MC4R-expressing neurons remains unknown. This study was to determine whether deleting LRP1 from MC4R-expressing neurons affects adiposity and energy balance in mice. Here we show that MC4R neuron-specific LRP1 deletion results in decreased body weight in mice fed a normal chow diet (control 30.4±0.8g vs. MC4R-LRP1 deficient mice 27.2±0.5g, p<0.05). Consistent with this, MRI analysis indicated that fat mass in MC4R-LRP1 deficient mice significantly decreased by ∼64% without changes in lean mass, compared with control mice. This occurred despite the fact that MC4R-LRP1 deficient mice are hyperphagic (control 3.99±0.17g vs. MC4R-LRP1 deficient mice 4.71±0.18g, p<0.05). In addition, MTII’s ability to suppress food intake was impaired in MC4R-LRP1 deficient mice. These effects are mainly due to increased energy metabolism, as evidenced by the fact that oxygen consumption for 24 hours increased in MC4R-LRP1 deficient mice compared with control mice (control mice 6002±287 ml/kg/hour vs. MC4R-LRP1 deficient mice 7121±1947 ml/kg/hour, p<0.01), along with exhibiting insulin sensitivity and glucose tolerance. However, locomotor activity was normal in these mice. The current data demonstrate that LRP1 signaling in MC4R neurons is required for the homeostatic regulation of energy expenditure and adiposity. Thus, LRP1 is a key player of energy balance in MC4R-expressing neurons. Disclosure M. Kang: None. J.A. Seo: None. H. Cho: None. H. Lee: None. Y. Kim: None.