title: Loss of Atg12, but not Atg5, in pro-opiomelanocortin neurons exacerbates diet-induced obesity.
abstract: The autophagy-related proteins ATG12 and ATG5 form a covalent complex essential for autophagy. Here, we demonstrate that ATG12 has distinct functions from ATG5 in pro-opiomelanocortin (POMC)-expressing neurons. Upon high-fat diet (HFD) consumption, mice lacking Atg12 in POMC-positive neurons exhibit accelerated weight gain, adiposity, and glucose intolerance, which is associated with increased food intake, reduced ambulation, and decreased LEP/leptin sensitivity. Importantly, although genetic deletion of either Atg12 or Atg5 renders POMC neurons autophagy-deficient, mice lacking Atg5 in POMC neurons do not exhibit these phenotypes. Hence, we propose nonautophagic functions for ATG12 in POMC neurons that counteract excessive weight gain in response to HFD consumption.
authors.affiliation: a Department of Pathology and Helen Diller Family Comprehensive Cancer Center ; University of California ; San Francisco , CA USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Malhotra
authors.forename: James P
authors.initials: JP
authors.lastname: Warne
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salas
authors.forename: Allison W
authors.initials: AW
authors.lastname: Xu
authors.forename: Jayanta
authors.initials: J
authors.lastname: Debnath
mesh_terms: D050154:Adiposity; D000818:Animals; D000831:Animals, Newborn; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D001835:Body Weight; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005247:Feeding Behavior; D017353:Gene Deletion; D018390:Gene Targeting; D019426:Integrases / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
chemical_list: C491971:Atg12 protein, mouse; C495773:Atg5 protein, mouse; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D020738:Leptin; D008869:Microtubule-Associated Proteins; D011506:Proteins; D011333:Pro-Opiomelanocortin; C045073:Cre recombinase; D019426:Integrases
keywords: AGRP, agouti-related peptide; ATG12; ATG5; BAC, bacterial artificial chromosome; BMD, bone mineral density; BafA, bafilomycin A1; CLAMS, Comprehensive Lab Animal Monitoring System; DEXA, dual energy X-ray absorptiometry; HBSS, Hank's balanced salt solution; HFD, high-fat diet; LC3-II, phosphatidylethanolamine conjugated isoform of microtubule-associated protein 1 light chain 3; LEP, leptin; MAP1LC3, microtubule-associated protein 1 light chain 3; MEFs, mouse embryonic fibroblasts; NBR1, neighbor of BRCA1 gene 1; NPY, neuropeptide Y; PBS, phosphate-buffered saline; PE, phosphatidylethanolamine; POMC; POMC/ACTH, pro-opiomelanocortin-α (in mice), proopiomelanocortin (in humans); SQSTM1/p62, sequestosome 1; SV40Tag, simian virus 40 T antigen; UBL, ubiquitin-like molecule; autophagy; diet-induced obesity; hypothalamus; leptin; pSTAT3, phosphorylated form of signal transducer and activator of transcription 3 (acute-phase response factor)