Abstract
The hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons are crucial for the regulation of whole-body energy homeostasis. Here, we show that fasting-induced AgRP neuronal activation is associated with dynamin-related peptide 1 (DRP1)-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking Dnm1l in adult AgRP neurons (Drp1 cKO) show decreased fasting- or ghrelin-induced AgRP neuronal activity and feeding and exhibited a significant decrease in body weight, fat mass, and feeding accompanied by a significant increase in energy expenditure. In support of the role for mitochondrial fission and fatty acids oxidation, Drp1 cKO mice showed attenuated palmitic acid-induced mitochondrial respiration. Altogether, our data revealed that mitochondrial dynamics and fatty acids oxidation in hypothalamic AgRP neurons is a critical mechanism for AgRP neuronal function and body-weight regulation.
Highlights
The central nervous system (CNS) regulates whole-body energy metabolism through multiple neuronal networks (Diano, 2013; Myers and Olson, 2012)
We observed that compared to feeding (0.174 ± 0.007 mm2, p
Our findings revealed a crucial role of mitochondrial fission in AgRP neurons in the regulation of hypothalamic feeding control
Summary
The central nervous system (CNS) regulates whole-body energy metabolism through multiple neuronal networks (Diano, 2013; Myers and Olson, 2012). The anatomical location of the hypothalamic ARC allows these neurons to rapidly respond to fluctuations of numerous circulating metabolic signals, including nutrients and hormones (Gao and Horvath, 2007). Mitochondria are highly dynamic organelles able to change their morphology and location according to the needs of the cell (Chan, 2006). Previous studies from our laboratory have shown that NPY/AgRP neuronal activation is associated with changes in mitochondrial morphology and density during fasting or after ghrelin administration (Andrews et al, 2008; Coppola et al, 2007; Dietrich et al, 2013), suggesting that changes in mitochondrial dynamics play a role in the regulation of neuronal activation of these neurons (Nasrallah and Horvath, 2014). In the present study we interrogated the relevance of mitochondrial fission in AgRP neurons in relation to fuel availability
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