Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 5/2013

01-05-2013 | Review

Insulin signalling mechanisms for triacylglycerol storage

Authors: M. P. Czech, M. Tencerova, D. J. Pedersen, M. Aouadi

Published in: Diabetologia | Issue 5/2013

Login to get access

Abstract

Insulin signalling is uniquely required for storing energy as fat in humans. While de novo synthesis of fatty acids and triacylglycerol occurs mostly in liver, adipose tissue is the primary site for triacylglycerol storage. Insulin signalling mechanisms in adipose tissue that stimulate hydrolysis of circulating triacylglycerol, uptake of the released fatty acids and their conversion to triacylglycerol are poorly understood. New findings include (1) activation of DNA-dependent protein kinase to stimulate upstream stimulatory factor (USF)1/USF2 heterodimers, enhancing the lipogenic transcription factor sterol regulatory element binding protein 1c (SREBP1c); (2) stimulation of fatty acid synthase through AMP kinase modulation; (3) mobilisation of lipid droplet proteins to promote retention of triacylglycerol; and (4) upregulation of a novel carbohydrate response element binding protein β isoform that potently stimulates transcription of lipogenic enzymes. Additionally, insulin signalling through mammalian target of rapamycin to activate transcription and processing of SREBP1c described in liver may apply to adipose tissue. Paradoxically, insulin resistance in obesity and type 2 diabetes is associated with increased triacylglycerol synthesis in liver, while it is decreased in adipose tissue. This and other mysteries about insulin signalling and insulin resistance in adipose tissue make this topic especially fertile for future research.
Literature
1.
Tattersall RB (1995) A force of magical activity: the introduction of insulin treatment in Britain 1922–1926. Diabet Med 12:739–755PubMedCrossRef
2.
Dentin R, Girard J, Postic C (2005) Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87:81–86PubMedCrossRef
3.
Frayn KN (1998) Regulation of fatty acid delivery in vivo. Adv Exp Med Biol 441:171–179PubMed
4.
5.
Boden G (2001) Free fatty acids—the link between obesity and insulin resistance. Endocr Pract 7:44–51PubMedCrossRef
6.
Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267–2277PubMedCrossRef
7.
McGarry JD (1992) What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258:766–770PubMedCrossRef
8.
Chavez JA, Summers SA (2010) Lipid oversupply, selective insulin resistance, and lipotoxicity: molecular mechanisms. Biochim Biophys Acta 1801:252–265PubMedCrossRef
9.
Samuel VT, Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148:852–871PubMedCrossRef
10.
Dresner A, Laurent D, Marcucci M et al (1999) Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253–259PubMedCrossRef
11.
Holland WL, Bikman BT, Wang LP et al (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121:1858–1870PubMedCrossRef
12.
Hoy AJ, Brandon AE, Turner N et al (2009) Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation. Am J Physiol Endocrinol Metab 297:E67–E75PubMedCrossRef
13.
Roden M, Price TB, Perseghin G et al (1996) Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97:2859–2865PubMedCrossRef
14.
Schmitz-Peiffer C, Craig DL, Biden TJ (1999) Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 274:24202–24210PubMedCrossRef
15.
Sinha S, Perdomo G, Brown NF, O’Doherty RM (2004) Fatty acid-induced insulin resistance in L6 myotubes is prevented by inhibition of activation and nuclear localization of nuclear factor kappa B. J Biol Chem 279:41294–41301PubMedCrossRef
16.
Stratford S, Hoehn KL, Liu F, Summers SA (2004) Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 279:36608–36615PubMedCrossRef
17.
Karpe F, Dickmann JR, Frayn KN (2011) Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 60:2441–2449PubMedCrossRef
18.
Li P, Fan W, Xu J et al (2011) Adipocyte NCoR knockout decreases PPARgamma phosphorylation and enhances PPARgamma activity and insulin sensitivity. Cell 147:815–826PubMedCrossRef
19.
Sugii S, Olson P, Sears DD et al (2009) PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization. Proc Natl Acad Sci U S A 106:22504–22509PubMedCrossRef
20.
Chen HC, Stone SJ, Zhou P, Buhman KK, Farese RV Jr (2002) Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme A:diacylglycerol acyltransferase 1 in white adipose tissue. Diabetes 51:3189–3195PubMedCrossRef
21.
Herman MA, Peroni OD, Villoria J et al (2012) A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484:333–338PubMedCrossRef
22.
Kusminski CM, Holland WL, Sun K et al (2012) MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med 18:1539–1549PubMedCrossRef
23.
Shepherd PR, Gnudi L, Tozzo E, Yang H, Leach F, Kahn BB (1993) Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. J Biol Chem 268:22243–22246PubMed
24.
Brasaemle DL (2007) Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis. J Lipid Res 48:2547–2559PubMedCrossRef
25.
Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS (2007) Regulation of lipolysis in adipocytes. Annu Rev Nutr 27:79–101PubMedCrossRef
26.
Martinez-Botas J, Anderson JB, Tessier D et al (2000) Absence of perilipin results in leanness and reverses obesity in Lepr db/db mice. Nat Genet 26:474–479PubMedCrossRef
27.
Puri V, Konda S, Ranjit S et al (2007) Fat-specific protein 27, a novel lipid droplet protein that enhances triglyceride storage. J Biol Chem 282:34213–34218PubMedCrossRef
28.
Haemmerle G, Zimmermann R, Strauss JG et al (2002) Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle. J Biol Chem 277:12946–12952PubMedCrossRef
29.
Taschler U, Radner FP, Heier C et al (2011) Monoglyceride lipase deficiency in mice impairs lipolysis and attenuates diet-induced insulin resistance. J Biol Chem 286:17467–17477PubMedCrossRef
30.
Zechner R, Zimmermann R, Eichmann TO et al (2012) Fat signals—lipases and lipolysis in lipid metabolism and signaling. Cell Metab 15:279–291PubMedCrossRef
31.
Zimmermann R, Strauss JG, Haemmerle G et al (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306:1383–1386PubMedCrossRef
32.
Gruber A, Cornaciu I, Lass A et al (2010) The N-terminal region of comparative gene identification-58 (CGI-58) is important for lipid droplet binding and activation of adipose triglyceride lipase. J Biol Chem 285:12289–12298PubMedCrossRef
33.
Lass A, Zimmermann R, Haemmerle G et al (2006) Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab 3:309–319PubMedCrossRef
34.
Miyoshi H, Perfield JW 2nd, Souza SC et al (2007) Control of adipose triglyceride lipase action by serine 517 of perilipin A globally regulates protein kinase A-stimulated lipolysis in adipocytes. J Biol Chem 282:996–1002PubMedCrossRef
35.
Shen WJ, Patel S, Miyoshi H, Greenberg AS, Kraemer FB (2009) Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. J Lipid Res 50:2306–2313PubMedCrossRef
36.
Bordicchia M, Liu D, Amri EZ et al (2012) Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 122:1022–1036PubMedCrossRef
37.
Moro C, Galitzky J, Sengenes C, Crampes F, Lafontan M, Berlan M (2004) Functional and pharmacological characterization of the natriuretic peptide-dependent lipolytic pathway in human fat cells. J Pharmacol Exp Ther 308:984–992PubMedCrossRef
38.
Sengenes C, Berlan M, de Glisezinski I, Lafontan M, Galitzky J (2000) Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J 14:1345–1351PubMedCrossRef
39.
Sengenes C, Bouloumie A, Hauner H et al (2003) Involvement of a cGMP-dependent pathway in the natriuretic peptide-mediated hormone-sensitive lipase phosphorylation in human adipocytes. J Biol Chem 278:48617–48626PubMedCrossRef
40.
Wang TJ, Larson MG, Levy D et al (2004) Impact of obesity on plasma natriuretic peptide levels. Circulation 109:594–600PubMedCrossRef
41.
42.
Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96PubMedCrossRef
43.
Duncan RE, Sarkadi-Nagy E, Jaworski K, Ahmadian M, Sul HS (2008) Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA). J Biol Chem 283:25428–25436PubMedCrossRef
44.
Jaworski K, Ahmadian M, Duncan RE et al (2009) AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15:159–168PubMedCrossRef
45.
Eriksson H, Ridderstrale M, Degerman E et al (1995) Evidence for the key role of the adipocyte cGMP-inhibited cAMP phosphodiesterase in the antilipolytic action of insulin. Biochim Biophys Acta 1266:101–107PubMedCrossRef
46.
Kitamura T, Kitamura Y, Kuroda S et al (1999) Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol Cell Biol 19:6286–6296PubMed
47.
Rahn T, Ridderstrale M, Tornqvist H et al (1994) Essential role of phosphatidylinositol 3-kinase in insulin-induced activation and phosphorylation of the cGMP-inhibited cAMP phosphodiesterase in rat adipocytes. Studies using the selective inhibitor wortmannin. FEBS Lett 350:314–318PubMedCrossRef
48.
Chakrabarti P, English T, Shi J, Smas CM, Kandror KV (2010) Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 59:775–781PubMedCrossRef
49.
Kim JY, Liu K, Zhou S, Tillison K, Wu Y, Smas CM (2008) Assessment of fat-specific protein 27 in the adipocyte lineage suggests a dual role for FSP27 in adipocyte metabolism and cell death. Am J Physiol Endocrinol Metab 294:E654–E667PubMedCrossRef
50.
Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR (1994) Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp 70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14:4902–4911PubMed
51.
Cushman SW, Wardzala LJ (1980) Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane. J Biol Chem 255:4758–4762PubMed
52.
Guilherme A, Czech MP (1998) Stimulation of IRS-1-associated phosphatidylinositol 3-kinase and Akt/protein kinase B but not glucose transport by beta1-integrin signaling in rat adipocytes. J Biol Chem 273:33119–33122PubMedCrossRef
53.
54.
Suzuki K, Kono T (1980) Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc Natl Acad Sci U S A 77:2542–2545PubMedCrossRef
55.
Nye C, Kim J, Kalhan SC, Hanson RW (2008) Reassessing triglyceride synthesis in adipose tissue. Trends Endocrinol Metab 19:356–361PubMedCrossRef
56.
Farese RV, Sajan MP, Standaert ML (2005) Atypical protein kinase C in insulin action and insulin resistance. Biochem Soc Trans 33:350–353PubMedCrossRef
57.
Kotani K, Ogawa W, Matsumoto M et al (1998) Requirement of atypical protein kinase clambda for insulin stimulation of glucose uptake but not for Akt activation in 3T3-L1 adipocytes. Mol Cell Biol 18:6971–6982PubMed
58.
Cho H, Mu J, Kim JK et al (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728–1731PubMedCrossRef
59.
Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q, Czech MP (2003) Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc Natl Acad Sci U S A 100:7569–7574PubMedCrossRef
60.
Eguez L, Lee A, Chavez JA et al (2005) Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein. Cell Metab 2:263–272PubMedCrossRef
61.
Kane S, Sano H, Liu SC et al (2002) A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J Biol Chem 277:22115–22118PubMedCrossRef
62.
63.
Chen S, Wasserman DH, MacKintosh C, Sakamoto K (2011) Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking. Cell Metab 13:68–79PubMedCrossRef
64.
Gonzalez E, McGraw TE (2006) Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane. Mol Biol Cell 17:4484–4493PubMedCrossRef
65.
Picard F, Naimi N, Richard D, Deshaies Y (1999) Response of adipose tissue lipoprotein lipase to the cephalic phase of insulin secretion. Diabetes 48:452–459PubMedCrossRef
66.
Semenkovich CF, Wims M, Noe L, Etienne J, Chan L (1989) Insulin regulation of lipoprotein lipase activity in 3T3-L1 adipocytes is mediated at posttranscriptional and posttranslational levels. J Biol Chem 264:9030–9038PubMed
67.
Gonzales AM, Orlando RA (2007) Role of adipocyte-derived lipoprotein lipase in adipocyte hypertrophy. Nutr Metab (Lond) 4:22CrossRef
68.
Sadur CN, Eckel RH (1982) Insulin stimulation of adipose tissue lipoprotein lipase. Use of the euglycemic clamp technique. J Clin Invest 69:1119–1125PubMedCrossRef
69.
Yki-Jarvinen H, Taskinen MR, Koivisto VA, Nikkila EA (1984) Response of adipose tissue lipoprotein lipase activity and serum lipoproteins to acute hyperinsulinaemia in man. Diabetologia 27:364–369PubMedCrossRef
70.
Albalat A, Saera-Vila A, Capilla E, Gutierrez J, Perez-Sanchez J, Navarro I (2007) Insulin regulation of lipoprotein lipase (LPL) activity and expression in gilthead sea bream (Sparus aurata). Comp Biochem Physiol B Biochem Mol Biol 148:151–159PubMedCrossRef
71.
Kraemer FB, Takeda D, Natu V, Sztalryd C (1998) Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways. Metabolism 47:555–559PubMedCrossRef
72.
Wu Q, Ortegon AM, Tsang B, Doege H, Feingold KR, Stahl A (2006) FATP1 is an insulin-sensitive fatty acid transporter involved in diet-induced obesity. Mol Cell Biol 26:3455–3467PubMedCrossRef
73.
Stahl A, Evans JG, Pattel S, Hirsch D, Lodish HF (2002) Insulin causes fatty acid transport protein translocation and enhanced fatty acid uptake in adipocytes. Dev Cell 2:477–488PubMedCrossRef
74.
Daval M, Diot-Dupuy F, Bazin R et al (2005) Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J Biol Chem 280:25250–25257PubMedCrossRef
75.
Orci L, Cook WS, Ravazzola M et al (2004) Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci U S A 101:2058–2063PubMedCrossRef
76.
Sullivan JE, Brocklehurst KJ, Marley AE, Carey F, Carling D, Beri RK (1994) Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett 353:33–36PubMedCrossRef
77.
Berggreen C, Gormand A, Omar B, Degerman E, Goransson O (2009) Protein kinase B activity is required for the effects of insulin on lipid metabolism in adipocytes. Am J Physiol Endocrinol Metab 296:E635–E646PubMedCrossRef
78.
Jayakumar A, Tai MH, Huang WY et al (1995) Human fatty acid synthase: properties and molecular cloning. Proc Natl Acad Sci U S A 92:8695–8699PubMedCrossRef
79.
Smith S, Witkowski A, Joshi AK (2003) Structural and functional organization of the animal fatty acid synthase. Prog Lipid Res 42:289–317PubMedCrossRef
80.
An Z, Wang H, Song P, Zhang M, Geng X, Zou MH (2007) Nicotine-induced activation of AMP-activated protein kinase inhibits fatty acid synthase in 3T3L1 adipocytes: a role for oxidant stress. J Biol Chem 282:26793–26801PubMedCrossRef
81.
Wolins NE, Skinner JR, Schoenfish MJ, Tzekov A, Bensch KG, Bickel PE (2003) Adipocyte protein S3-12 coats nascent lipid droplets. J Biol Chem 278:37713–37721PubMedCrossRef
82.
Ariotti N, Murphy S, Hamilton NA et al (2012) Postlipolytic insulin-dependent remodeling of micro lipid droplets in adipocytes. Mol Biol Cell 23:1826–1837PubMedCrossRef
83.
Assimacopoulos-Jeannet F, Brichard S, Rencurel F, Cusin I, Jeanrenaud B (1995) In vivo effects of hyperinsulinemia on lipogenic enzymes and glucose transporter expression in rat liver and adipose tissues. Metabolism 44:228–233PubMedCrossRef
84.
Griffin MJ, Wong RH, Pandya N, Sul HS (2007) Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter. J Biol Chem 282:5453–5467PubMedCrossRef
85.
Kim JB, Sarraf P, Wright M et al (1998) Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J Clin Invest 101:1–9PubMedCrossRef
86.
Sul HS, Latasa MJ, Moon Y, Kim KH (2000) Regulation of the fatty acid synthase promoter by insulin. J Nutr 130:315S–320SPubMed
87.
Kim JB, Spiegelman BM (1996) ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 10:1096–1107PubMedCrossRef
88.
Shimomura I, Shimano H, Korn BS, Bashmakov Y, Horton JD (1998) Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem 273:35299–35306PubMedCrossRef
89.
Wang X, Sato R, Brown MS, Hua X, Goldstein JL (1994) SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77:53–62PubMedCrossRef
90.
Yabe D, Komuro R, Liang G, Goldstein JL, Brown MS (2003) Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty acid synthesis. Proc Natl Acad Sci U S A 100:3155–3160PubMedCrossRef
91.
Amemiya-Kudo M, Shimano H, Yoshikawa T et al (2000) Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J Biol Chem 275:31078–31085PubMedCrossRef
92.
Im SS, Kwon SK, Kang SY et al (2006) Regulation of GLUT4 gene expression by SREBP-1c in adipocytes. Biochem J 399:131–139PubMedCrossRef
93.
Tabor DE, Kim JB, Spiegelman BM, Edwards PA (1999) Identification of conserved cis-elements and transcription factors required for sterol-regulated transcription of stearoyl-CoA desaturase 1 and 2. J Biol Chem 274:20603–20610PubMedCrossRef
94.
Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL (1997) Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 99:846–854PubMedCrossRef
95.
Shimano H, Shimomura I, Hammer RE et al (1997) Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest 100:2115–2124PubMedCrossRef
96.
Taniguchi CM, Kondo T, Sajan M et al (2006) Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab 3:343–353PubMedCrossRef
97.
Matsumoto M, Ogawa W, Akimoto K et al (2003) PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. J Clin Invest 112:935–944PubMed
98.
Peterson TR, Sengupta SS, Harris TE et al (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146:408–420PubMedCrossRef
99.
Quinn WJ 3rd, Birnbaum MJ (2012) Distinct mTORC1 pathways for transcription and cleavage of SREBP-1c. Proc Natl Acad Sci U S A 109:15974–15975PubMedCrossRef
100.
Yecies JL, Zhang HH, Menon S et al (2011) Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 14:21–32PubMedCrossRef
101.
Bae EJ, Xu J, da Oh Y et al (2012) Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance. J Biol Chem 287:18769–18780PubMedCrossRef
102.
Li S, Ogawa W, Emi A et al (2011) Role of S6K1 in regulation of SREBP1c expression in the liver. Biochem Biophys Res Commun 412:197–202PubMedCrossRef
103.
Goldstein JL, DeBose-Boyd RA, Brown MS (2006) Protein sensors for membrane sterols. Cell 124:35–46PubMedCrossRef
104.
Kotzka J, Knebel B, Haas J et al (2012) Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. PLoS One 7:e32609PubMedCrossRef
105.
Roth G, Kotzka J, Kremer L et al (2000) MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro. J Biol Chem 275:33302–33307PubMedCrossRef
106.
Casado M, Vallet VS, Kahn A, Vaulont S (1999) Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J Biol Chem 274:2009–2013PubMedCrossRef
107.
Brady MJ, Saltiel AR (2001) The role of protein phosphatase-1 in insulin action. Recent Prog Horm Res 56:157–173PubMedCrossRef
108.
Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS (2009) A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell 136:1056–1072PubMedCrossRef
109.
Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K (2004) Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A 101:7281–7286PubMedCrossRef
110.
Ma L, Robinson LN, Towle HC (2006) ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem 281:28721–28730PubMedCrossRef
111.
Stoeckman AK, Ma L, Towle HC (2004) Mlx is the functional heteromeric partner of the carbohydrate response element-binding protein in glucose regulation of lipogenic enzyme genes. J Biol Chem 279:15662–15669PubMedCrossRef
112.
Yamashita H, Takenoshita M, Sakurai M et al (2001) A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci U S A 98:9116–9121PubMedCrossRef
113.
Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K (2002) Mechanism for fatty acid ‘sparing’ effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. J Biol Chem 277:3829–3835PubMedCrossRef
114.
Dentin R, Tomas-Cobos L, Foufelle F et al (2012) Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. J Hepatol 56:199–209PubMedCrossRef
115.
Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS (2008) Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134:933–944PubMedCrossRef
116.
Bluher M, Michael MD, Peroni OD et al (2002) Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 3:25–38PubMedCrossRef
117.
Boucher J, Mori MA, Lee KY et al (2012) Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling. Nat Commun 3:902PubMedCrossRef
118.
Elgazar-Carmon V, Rudich A, Hadad N, Levy R (2008) Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 49:1894–1903PubMedCrossRef
119.
Liu J, Divoux A, Sun J et al (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15:940–945PubMedCrossRef
120.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808PubMed
121.
Winer DA, Winer S, Shen L et al (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17:610–617PubMedCrossRef
122.
Wu D, Molofsky AB, Liang HE et al (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332:243–247PubMedCrossRef
123.
Wu L, Parekh VV, Gabriel CL et al (2012) Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc Natl Acad Sci U S A 109:E1143–E1152PubMedCrossRef
124.
Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW (2004) Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145:2273–2282PubMedCrossRef
125.
Lumeng CN, Deyoung SM, Saltiel AR (2007) Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 292:E166–E174PubMedCrossRef
126.
Suganami T, Tanimoto-Koyama K, Nishida J et al (2007) Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol 27:84–91PubMedCrossRef
127.
Kosteli A, Sugaru E, Haemmerle G et al (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120:3466–3479PubMedCrossRef
128.
Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184PubMedCrossRef
129.
Prieur X, Mok CY, Velagapudi VR et al (2011) Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60:797–809PubMedCrossRef
130.
Suganami T, Nishida J, Ogawa Y (2005) A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25:2062–2068PubMedCrossRef
131.
Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929PubMedCrossRef
132.
Wu H, Ghosh S, Perrard XD et al (2007) T cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115:1029–1038PubMedCrossRef
133.
Deiuliis J, Shah Z, Shah N et al (2011) Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 6:e16376PubMedCrossRef
134.
Duffaut C, Zakaroff-Girard A, Bourlier V et al (2009) Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators. Arterioscler Thromb Vasc Biol 29:1608–1614PubMedCrossRef
135.
Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939PubMedCrossRef
136.
Nishimura S, Manabe I, Nagasaki M et al (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920PubMedCrossRef
137.
Winer S, Paltser G, Chan Y et al (2009) Obesity predisposes to Th17 bias. Eur J Immunol 39:2629–2635PubMedCrossRef
138.
Jagannathan-Bogdan M, McDonnell ME, Shin H et al (2011) Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 186:1162–1172PubMedCrossRef
139.
Zuniga LA, Shen WJ, Joyce-Shaikh B et al (2010) IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 185:6947–6959PubMedCrossRef
140.
Ohmura K, Ishimori N, Ohmura Y et al (2010) Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler Thromb Vasc Biol 30:193–199PubMedCrossRef
141.
Tabas I, Tall A, Accili D (2010) The impact of macrophage insulin resistance on advanced atherosclerotic plaque progression. Circ Res 106:58–67PubMedCrossRef
142.
Mauer J, Chaurasia B, Plum L et al (2010) Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance. PLoS Genet 6:e1000938PubMedCrossRef
143.
Baumgartl J, Baudler S, Scherner M et al (2006) Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis. Cell Metab 3:247–256PubMedCrossRef
144.
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614PubMedCrossRef
145.
Ji C, Chen X, Gao C et al (2011) IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes. J Bioenerg Biomembr 43:367–375PubMedCrossRef
146.
Lang CH, Dobrescu C, Bagby GJ (1992) Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130:43–52PubMedCrossRef
147.
Rask-Madsen C, Dominguez H, Ihlemann N, Hermann T, Kober L, Torp-Pedersen C (2003) Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Circulation 108:1815–1821PubMedCrossRef
148.
Xu H, Hirosumi J, Uysal KT, Guler AD, Hotamisligil GS (2002) Exclusive action of transmembrane TNF alpha in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance. Endocrinology 143:1502–1511PubMedCrossRef
149.
McGillicuddy FC, Chiquoine EH, Hinkle CC et al (2009) Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem 284:31936–31944PubMedCrossRef
150.
Rocha VZ, Folco EJ, Sukhova G et al (2008) Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 103:467–476PubMedCrossRef
151.
Chakrabarti SK, Cole BK, Wen Y, Keller SR, Nadler JL (2009) 12/15-Lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes. Obesity (Silver Spring) 17:1657–1663CrossRef
152.
Horrillo R, Gonzalez-Periz A, Martinez-Clemente M et al (2010) 5-Lipoxygenase activating protein signals adipose tissue inflammation and lipid dysfunction in experimental obesity. J Immunol 184:3978–3987PubMedCrossRef
153.
Lucas S, Taront S, Magnan C et al (2012) Interleukin-7 regulates adipose tissue mass and insulin sensitivity in high-fat diet-fed mice through lymphocyte-dependent and independent mechanisms. PLoS One 7:e40351PubMedCrossRef
154.
Miller AM, Asquith DL, Hueber AJ et al (2010) Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ Res 107:650–658PubMedCrossRef
155.
Chavey C, Lazennec G, Lagarrigue S et al (2009) CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance. Cell Metab 9:339–349PubMedCrossRef
156.
Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI et al (2010) IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 107:22617–22622PubMedCrossRef
157.
Levings MK, Schrader JW (1999) IL-4 inhibits the production of TNF-alpha and IL-12 by STAT6-dependent and -independent mechanisms. J Immunol 162:5224–5229PubMed
158.
Smallie T, Ricchetti G, Horwood NJ, Feldmann M, Clark AR, Williams LM (2010) IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. J Exp Med 207:2081–2088PubMedCrossRef
159.
Hong EG, Ko HJ, Cho YR et al (2009) Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes 58:2525–2535PubMedCrossRef
160.
Chang YH, Ho KT, Lu SH, Huang CN, Shiau MY (2012) Regulation of glucose/lipid metabolism and insulin sensitivity by interleukin-4. Int J Obes (Lond) 36:993–998CrossRef
161.
Olefsky JM (1976) Decreased insulin binding to adipocytes and circulating monocytes from obese subjects. J Clin Invest 57:1165–1172PubMedCrossRef
162.
Olefsky JM, Reaven GM (1975) Effects of age and obesity on insulin binding to isolated adipocytes. Endocrinology 96:1486–1498PubMedCrossRef
163.
Grako KA, Olefsky JM, McClain DA (1992) Tyrosine kinase-defective insulin receptors undergo decreased endocytosis but do not affect internalization of normal endogenous insulin receptors. Endocrinology 130:3441–3452PubMedCrossRef
164.
Garvey WT, Olefsky JM, Marshall S (1985) Insulin receptor down-regulation is linked to an insulin-induced postreceptor defect in the glucose transport system in rat adipocytes. J Clin Invest 76:22–30PubMedCrossRef
165.
Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl 2):S262–S268PubMedCrossRef
166.
Czech MP (1976) Cellular basis of insulin insensitivity in large rat adipocytes. J Clin Invest 57:1523–1532PubMedCrossRef
167.
Carvalho E, Rondinone C, Smith U (2000) Insulin resistance in fat cells from obese Zucker rats—evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4. Mol Cell Biochem 206:7–16PubMedCrossRef
168.
Shao J, Yamashita H, Qiao L, Friedman JE (2000) Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. J Endocrinol 167:107–115PubMedCrossRef
169.
Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM (1987) Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. J Clin Invest 79:240–250PubMedCrossRef
170.
Carvalho E, Eliasson B, Wesslau C, Smith U (2000) Impaired phosphorylation and insulin-stimulated translocation to the plasma membrane of protein kinase B/Akt in adipocytes from type II diabetic subjects. Diabetologia 43:1107–1115PubMedCrossRef
171.
Cleveland-Donovan K, Maile LA, Tsiaras WG, Tchkonia T, Kirkland JL, Boney CM (2010) IGF-I activation of the AKT pathway is impaired in visceral but not subcutaneous preadipocytes from obese subjects. Endocrinology 151:3752–3763PubMedCrossRef
172.
Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205PubMedCrossRef
173.
Dibble CC, Asara JM, Manning BD (2009) Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 29:5657–5670PubMedCrossRef
174.
Ishibashi KI, Imamura T, Sharma PM, Huang J, Ugi S, Olefsky JM (2001) Chronic endothelin-1 treatment leads to heterologous desensitization of insulin signaling in 3T3-L1 adipocytes. J Clin Invest 107:1193–1202PubMedCrossRef
175.
Usui I, Imamura T, Babendure JL et al (2005) G protein-coupled receptor kinase 2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1 pathways in 3T3-L1 adipocytes. Mol Endocrinol 19:2760–2768PubMedCrossRef
176.
Kreier F, Fliers E, Voshol PJ et al (2002) Selective parasympathetic innervation of subcutaneous and intra-abdominal fat—functional implications. J Clin Invest 110:1243–1250PubMed
177.
Zvonic S, Cornelius P, Stewart WC, Mynatt RL, Stephens JM (2003) The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. J Biol Chem 278:2228–2235PubMedCrossRef
178.
Scherer T, O’Hare J, Diggs-Andrews K et al (2011) Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 13:183–194PubMedCrossRef
179.
Ajuwon KM, Spurlock ME (2005) Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNF alpha expression in 3T3-L1 adipocytes. J Nutr 135:1841–1846PubMed
180.
Hunnicutt JW, Hardy RW, Williford J, McDonald JM (1994) Saturated fatty acid-induced insulin resistance in rat adipocytes. Diabetes 43:540–545PubMedCrossRef
181.
Dandona P, Aljada A, Mohanty P et al (2001) Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86:3257–3265PubMedCrossRef
182.
Dandona P, Chaudhuri A, Mohanty P, Ghanim H (2007) Anti-inflammatory effects of insulin. Curr Opin Clin Nutr Metab Care 10:511–517PubMedCrossRef
183.
Viardot A, Grey ST, Mackay F, Chisholm D (2007) Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. Endocrinology 148:346–353PubMedCrossRef
184.
Ghanim H, Korzeniewski K, Sia CL et al (2010) Suppressive effect of insulin infusion on chemokines and chemokine receptors. Diabetes Care 33:1103–1108PubMedCrossRef
185.
Iida KT, Shimano H, Kawakami Y et al (2001) Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway. J Biol Chem 276:32531–32537PubMedCrossRef
186.
McTernan PG, Harte AL, Anderson LA et al (2002) Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro. Diabetes 51:1493–1498PubMedCrossRef
187.
Soop M, Duxbury H, Agwunobi AO et al (2002) Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans. Am J Physiol Endocrinol Metab 282:E1276–E1285PubMed
188.
Siklova-Vitkova M, Polak J, Klimcakova E et al (2009) Effect of hyperinsulinemia and very-low-calorie diet on interstitial cytokine levels in subcutaneous adipose tissue of obese women. Am J Physiol Endocrinol Metab 297:E1154–E1161PubMedCrossRef
189.
Odegaard JI, Chawla A (2008) Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab 4:619–626PubMedCrossRef
190.
Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18:363–374PubMedCrossRef
191.
Ye J (2008) Regulation of PPARgamma function by TNF-alpha. Biochem Biophys Res Commun 374:405–408PubMedCrossRef
192.
Czech MP (1976) Regulation of the d-glucose transport system in isolated fat cells. Mol Cell Biochem 11:51–63PubMedCrossRef
193.
Hoehn KL, Turner N, Cooney GJ, James DE (2012) Phenotypic discrepancies in acetyl-CoA carboxylase 2-deficient mice. J Biol Chem 287:15801, Author reply, 287:15802PubMedCrossRef
194.
Shirakami A, Toyonaga T, Tsuruzoe K et al (2002) Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. J Endocrinol 174:309–319PubMedCrossRef
195.
Cleasby ME, Reinten TA, Cooney GJ, James DE, Kraegen EW (2007) Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. Mol Endocrinol 21:215–228PubMedCrossRef
196.
Diraison F, Dusserre E, Vidal H, Sothier M, Beylot M (2002) Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity. Am J Physiol Endocrinol Metab 282:E46–E51PubMed
197.
Ortega FJ, Mayas D, Moreno-Navarrete JM et al (2010) The gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue of obese subjects. Obesity (Silver Spring) 18:13–20CrossRef
198.
Lan H, Rabaglia ME, Stoehr JP et al (2003) Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility. Diabetes 52:688–700PubMedCrossRef
199.
Nadler ST, Stoehr JP, Schueler KL, Tanimoto G, Yandell BS, Attie AD (2000) The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proc Natl Acad Sci U S A 97:11371–11376PubMedCrossRef
200.
Kolehmainen M, Vidal H, Alhava E, Uusitupa MI (2001) Sterol regulatory element binding protein 1c (SREBP-1c) expression in human obesity. Obes Res 9:706–712PubMedCrossRef
201.
Ducluzeau PH, Perretti N, Laville M et al (2001) Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 50:1134–1142PubMedCrossRef
202.
Sewter C, Berger D, Considine RV et al (2002) Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. Diabetes 51:1035–1041PubMedCrossRef
203.
Clementi AH, Gaudy AM, van Rooijen N, Pierce RH, Mooney RA (2009) Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim Biophys Acta 1792:1062–1072PubMedCrossRef
204.
Cai D, Yuan M, Frantz DF et al (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190PubMedCrossRef
205.
Roche HM, Noone E, Sewter C et al (2002) Isomer-dependent metabolic effects of conjugated linoleic acid: insights from molecular markers sterol regulatory element-binding protein-1c and LXRalpha. Diabetes 51:2037–2044PubMedCrossRef
206.
Endo M, Masaki T, Seike M, Yoshimatsu H (2007) TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med (Maywood) 232:614–621
207.
Lawler JF Jr, Yin M, Diehl AM, Roberts E, Chatterjee S (1998) Tumor necrosis factor-alpha stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase. J Biol Chem 273:5053–5059PubMedCrossRef
208.
Zhang B, Berger J, Hu E et al (1996) Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol 10:1457–1466PubMedCrossRef
209.
Xing H, Northrop JP, Grove JR, Kilpatrick KE, Su JL, Ringold GM (1997) TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression. Endocrinology 138:2776–2783PubMedCrossRef
210.
Suzawa M, Takada I, Yanagisawa J et al (2003) Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. Nat Cell Biol 5:224–230PubMedCrossRef
211.
Festuccia WT, Blanchard PG, Turcotte V et al (2009) Depot-specific effects of the PPARgamma agonist rosiglitazone on adipose tissue glucose uptake and metabolism. J Lipid Res 50:1185–1194PubMedCrossRef
212.
Festuccia WT, Blanchard PG, Turcotte V et al (2009) The PPARgamma agonist rosiglitazone enhances rat brown adipose tissue lipogenesis from glucose without altering glucose uptake. Am J Physiol Regul Integr Comp Physiol 296:R1327–R1335PubMedCrossRef
213.
Laplante M, Sell H, MacNaul KL, Richard D, Berger JP, Deshaies Y (2003) PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion. Diabetes 52:291–299PubMedCrossRef
214.
Bickel PE, Tansey JT, Welte MA (2009) PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores. Biochim Biophys Acta 1791:419–440PubMedCrossRef
215.
Dalen KT, Schoonjans K, Ulven SM et al (2004) Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma. Diabetes 53:1243–1252PubMedCrossRef
216.
Wolins NE, Quaynor BK, Skinner JR et al (2006) OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization. Diabetes 55:3418–3428PubMedCrossRef
217.
Su D, Coudriet GM, Hyun Kim D et al (2009) FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages. Diabetes 58:2624–2633PubMedCrossRef
218.
Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE (2010) The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 152:346–357PubMed
219.
Larsen CM, Faulenbach M, Vaag A et al (2007) Interleukin-1 receptor antagonist-treatment of patients with type 2 diabetes. Ugeskr Laeger 169:3868–3871 [article in Danish]
220.
Stanley TL, Zanni MV, Johnsen S et al (2011) TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 96:E146–E150PubMedCrossRef
221.
Letexier D, Peroni O, Pinteur C, Beylot M (2005) In vivo expression of carbohydrate responsive element binding protein in lean and obese rats. Diabetes Metab 31:558–566PubMedCrossRef
222.
He Z, Jiang T, Wang Z, Levi M, Li J (2004) Modulation of carbohydrate response element-binding protein gene expression in 3T3-L1 adipocytes and rat adipose tissue. Am J Physiol Endocrinol Metab 287:E424–E430PubMedCrossRef
223.
Hurtado del Pozo C, Vesperinas-Garcia G, Rubio MA et al (2011) ChREBP expression in the liver, adipose tissue and differentiated preadipocytes in human obesity. Biochim Biophys Acta 1811:1194–1200PubMedCrossRef
224.
Koranyi L, James D, Mueckler M, Permutt MA (1990) Glucose transporter levels in spontaneously obese (db/db) insulin-resistant mice. J Clin Invest 85:962–967PubMedCrossRef
225.
Garvey WT, Maianu L, Huecksteadt TP, Birnbaum MJ, Molina JM, Ciaraldi TP (1991) Pretranslational suppression of a glucose transporter protein causes insulin resistance in adipocytes from patients with non-insulin-dependent diabetes mellitus and obesity. J Clin Invest 87:1072–1081PubMedCrossRef
226.
Lodhi IJ, Yin L, Jensen-Urstad AP et al (2012) Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARgamma activation to decrease diet-induced obesity. Cell Metab 16:189–201PubMedCrossRef
227.
Liu LH, Wang XK, Hu YD, Kang JL, Wang LL, Li S (2004) Effects of a fatty acid synthase inhibitor on adipocyte differentiation of mouse 3T3-L1 cells. Acta Pharmacol Sin 25:1052–1057PubMed
228.
Schmid B, Rippmann JF, Tadayyon M, Hamilton BS (2005) Inhibition of fatty acid synthase prevents preadipocyte differentiation. Biochem Biophys Res Commun 328:1073–1082PubMedCrossRef
229.
Jiang G, Dallas-Yang Q, Li Z et al (2002) Potentiation of insulin signaling in tissues of Zucker obese rats after acute and long-term treatment with PPARgamma agonists. Diabetes 51:2412–2419PubMedCrossRef
230.
Jiang G, Dallas-Yang Q, Biswas S, Li Z, Zhang BB (2004) Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. Biochem J 377:339–346PubMedCrossRef
231.
Leonardini A, Laviola L, Perrini S, Natalicchio A, Giorgino F (2009) Cross-talk between PPARgamma and insulin signaling and modulation of insulin sensitivity. PPAR Res 2009:818945PubMedCrossRef
232.
Yang X, Zhang X, Heckmann BL, Lu X, Liu J (2011) Relative contribution of adipose triglyceride lipase and hormone-sensitive lipase to tumor necrosis factor-alpha (TNF-alpha)-induced lipolysis in adipocytes. J Biol Chem 286:40477–40485PubMedCrossRef
233.
Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665–668PubMedCrossRef
234.
Chen X, Xun K, Chen L, Wang Y (2009) TNF-alpha, a potent lipid metabolism regulator. Cell Biochem Funct 27:407–416PubMedCrossRef
235.
Weiner FR, Smith PJ, Wertheimer S, Rubin CS (1991) Regulation of gene expression by insulin and tumor necrosis factor alpha in 3T3-L1 cells. Modulation of the transcription of genes encoding acyl-CoA synthetase and stearoyl-CoA desaturase-1. J Biol Chem 266:23525–23528PubMed
236.
Delikat SE, Galvani DW, Zuzel M (1995) The metabolic effects of interleukin 1 beta on human bone marrow adipocytes. Cytokine 7:338–343PubMedCrossRef
237.
McGillicuddy FC, Harford KA, Reynolds CM et al (2011) Lack of interleukin-1 receptor I (IL-1RI) protects mice from high-fat diet-induced adipose tissue inflammation coincident with improved glucose homeostasis. Diabetes 60:1688–1698PubMedCrossRef
238.
de Roos B, Rungapamestry V, Ross K et al (2009) Attenuation of inflammation and cellular stress-related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knockout mice on a high-fat diet. Proteomics 9:3244–3256PubMedCrossRef
239.
Lagathu C, Bastard JP, Auclair M, Maachi M, Capeau J, Caron M (2003) Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun 311:372–379PubMedCrossRef
240.
Matthews VB, Allen TL, Risis S et al (2010) Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53:2431–2441PubMedCrossRef
241.
Di Gregorio GB, Hensley L, Lu T, Ranganathan G, Kern PA (2004) Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity. Am J Physiol Endocrinol Metab 287:E182–E187PubMedCrossRef
242.
O’Rourke RW, White AE, Metcalf MD et al (2012) Systemic inflammation and insulin sensitivity in obese IFN-gamma knockout mice. Metabolism 61:1152–1161PubMedCrossRef
243.
Kowalski GM, Nicholls HT, Risis S et al (2011) Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice. Diabetologia 54:888–899PubMedCrossRef
244.
Perrier S, Darakhshan F, Hajduch E (2006) IL-1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde? FEBS Lett 580:6289–6294PubMedCrossRef
245.
Sauter NS, Schulthess FT, Galasso R, Castellani LW, Maedler K (2008) The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. Endocrinology 149:2208–2218PubMedCrossRef
246.
Somm E, Henrichot E, Pernin A et al (2005) Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure. Diabetes 54:3503–3509PubMedCrossRef
Metadata
Title
Insulin signalling mechanisms for triacylglycerol storage
Authors
M. P. Czech
M. Tencerova
D. J. Pedersen
M. Aouadi
Publication date
01-05-2013
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 5/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-2869-1

Other articles of this Issue 5/2013

Diabetologia 5/2013 Go to the issue

Article

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Article

Role of the EGF receptor in PPARγ-mediated sodium and water transport in human proximal tubule cells

Article

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

Erratum

Erratum to: Transcriptomes of the major human pancreatic cell types

Article

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Article

Absorption patterns of meals containing complex carbohydrates in type 1 diabetes

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits