Proteome and Phosphoproteome Analysis of Brown Adipocytes Reveals That RICTOR Loss Dampens Global Insulin/AKT Signaling

Abstract

Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 is important for regulating BAT metabolism, but its downstream targets have not been fully characterized. In this study, we apply proteomics and phosphoproteomics to investigate the downstream effectors of mTORC2 in brown adipocytes. We compare wild-type controls to isogenic cells with an induced knockout of the mTORC2 subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30-min time course. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation. We also observe significant differences to basal phosphorylation because of chronic RICTOR loss including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. Finally, we observe mild dampening of acute insulin signaling response in Rictor-iKO cells, and a subset of AKT substrates exhibiting statistically significant dependence on RICTOR. Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 is important for regulating BAT metabolism, but its downstream targets have not been fully characterized. In this study, we apply proteomics and phosphoproteomics to investigate the downstream effectors of mTORC2 in brown adipocytes. We compare wild-type controls to isogenic cells with an induced knockout of the mTORC2 subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30-min time course. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation. We also observe significant differences to basal phosphorylation because of chronic RICTOR loss including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. Finally, we observe mild dampening of acute insulin signaling response in Rictor-iKO cells, and a subset of AKT substrates exhibiting statistically significant dependence on RICTOR. The mammalian target of rapamycin (mTOR) 1The abbreviations used are:mTORmammalian target of rapamycinmTORC1mTOR complex 1mTORC2mTOR complex 2BATbrown adipose tissueDNLde novo lipogenesisACLYATP citrate lyaseVIMvimentinEIF4Beukaryotic translation initiation factor 4B. 1The abbreviations used are:mTORmammalian target of rapamycinmTORC1mTOR complex 1mTORC2mTOR complex 2BATbrown adipose tissueDNLde novo lipogenesisACLYATP citrate lyaseVIMvimentinEIF4Beukaryotic translation initiation factor 4B. is a serine/threonine kinase and a critical regulator of metabolism and cell growth. mTOR exists in two protein complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are commonly defined by their regulatory subunits, RAPTOR and RICTOR, respectively. Of the two complexes, mTORC2 is less well understood, though it is essential for development, the metabolic functions of many tissues, and the progression of certain tumors (1Saxton R.A. Sabatini D.M. mTOR signaling in growth, metabolism, and disease.Cell. 2017; 168: 960-976Abstract Full Text Full Text PDF PubMed Scopus (2169) Google Scholar, 2Lee P.L. Jung S.M. Guertin D.A. The complex roles of mechanistic target of rapamycin in adipocytes and beyond.Trends Endocrinol. Metab. 2017; 28: 319-339Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). In brown adipose tissue (BAT), mTORC2 is a key regulator of lipid metabolism. Tissue-specific knockout of Rictor in mouse BAT inhibits de novo lipogenesis (DNL), and increases lipid uptake, catabolic gene and UCP1 expression (3Jung S.M. Hung C.-M. Hildebrand S.R. Sanchez-Gurmaches J. Martinez-Pastor B. Gengatharan J.M. Wallace M. Mukhopadhyay D. Martinez Calejman C. Guertin D.A. mTORC2 signaling brown lipid Full Text Full Text PDF PubMed Scopus Google Scholar, C.-M. Calejman Sanchez-Gurmaches J. Guertin D.A. loss in the brown metabolism and and metabolic Full Text Full Text PDF PubMed Scopus Google Scholar). Rictor knockout in BAT and in the and of loss in BAT are to be (3Jung S.M. Hung C.-M. Hildebrand S.R. Sanchez-Gurmaches J. Martinez-Pastor B. Gengatharan J.M. Wallace M. Mukhopadhyay D. Martinez Calejman C. Guertin D.A. mTORC2 signaling brown lipid Full Text Full Text PDF PubMed Scopus Google Scholar, Calejman C. Jung S.M. Hung J. Guertin D.A. signaling to brown and de novo PubMed Scopus Google the of and functions that are is not mammalian target of rapamycin mTOR complex 1 mTOR complex 2 brown adipose tissue de novo lipogenesis citrate translation initiation factor 4B. mammalian target of rapamycin mTOR complex 1 mTOR complex 2 brown adipose tissue de novo lipogenesis citrate translation initiation factor 4B. mTORC2 the of and In AKT is upon by insulin and and AKT phosphorylation in in by mTORC2 phosphorylation of the in in by J. that Metab. Full Text Full Text PDF PubMed Scopus Google Scholar, M. phosphoproteomics in insulin signaling PubMed Scopus Google Scholar). phosphorylation is for in AKT activity M. B. of of protein kinase by insulin and J. PubMed Scopus Google Scholar). in essential mTORC2 have been on the phosphorylation of AKT with C.-M. Calejman Sanchez-Gurmaches J. Guertin D.A. loss in the brown metabolism and and metabolic Full Text Full Text PDF PubMed Scopus Google Scholar, Calejman C. Jung S.M. Hung J. Guertin D.A. signaling to brown and de novo PubMed Scopus Google Scholar, D. Jung J. B. complex and phosphorylation and Full Text Full Text PDF PubMed Scopus Google Scholar, D.A. D.M. J. M. Sabatini D.M. in of the or that mTORC2 is for signaling to and but not Full Text Full Text PDF PubMed Scopus Google Scholar, C. 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