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Cell Metab. 2016 Jan 12;23(1):113-27. doi: 10.1016/j.cmet.2015.10.008. Epub 2015 Nov 19.

Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver.

Author information

1
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
2
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3
Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy.
4
Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy.
5
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
6
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: rajat.singh@einstein.yu.edu.

Abstract

The integrative physiology of inter-organ communication in lipophagy regulation is not well understood. Lipophagy and the cytosolic lipases ATGL and HSL contribute to lipid droplet (LD) mobilization; however, whether autophagy proteins engage with lipases to promote lipid utilization remains unknown. Here, we show that cold induces autophagy in proopiomelanocortin (POMC) neurons and activates lipophagy in brown adipose tissue (BAT) and liver in mice. Targeted activation of autophagy in POMC neurons via intra-hypothalamic rapamycin is sufficient to trigger lipid utilization in room temperature-housed mice. Conversely, inhibiting autophagy in POMC neurons or in peripheral tissues or denervating BAT blocks lipid utilization. Unexpectedly, the autophagosome marker LC3 is mechanistically coupled to ATGL-mediated lipolysis. ATGL exhibits LC3-interacting region (LIR) motifs, and mutating a single LIR motif on ATGL displaces ATGL from LD and disrupts lipolysis. Thus, cold-induced activation of central autophagy activates lipophagy and cytosolic lipases in a complementary manner to mediate lipolysis in peripheral tissues.

PMID:
26698918
PMCID:
PMC4715637
DOI:
10.1016/j.cmet.2015.10.008
[Indexed for MEDLINE]
Free PMC Article

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