Haeusler, R. A., McGraw, T. E. & Accili, D. Biochemical and cellular properties of insulin receptor signalling. Nat. Rev. Mol. Cell Biol. 19, 31–44 (2018).
Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85–96 (2006).
Martini, M., De Santis, M. C., Braccini, L., Gulluni, F. & Hirsch, E. PI3K/AKT signaling pathway and cancer: an updated review. Ann. Med. 46, 372–383 (2014).
Dennis, E. A. & Norris, P. C. Eicosanoid storm in infection and inflammation. Nat. Rev. Immunol. 15, 511–523 (2015).
Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nat. Rev. Mol. Cell Biol. 9, 162–176 (2008).
Chavez, J. A. & Summers, S. A. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch. Biochem. Biophys. 419, 101–109 (2003).
Davis, J. E., Gabler, N. K., Walker-Daniels, J. & Spurlock, M. E. The c-Jun N-terminal kinase mediates the induction of oxidative stress and insulin resistance by palmitate and toll-like receptor 2 and 4 ligands in 3T3-L1 adipocytes. Horm. Metab. Res. 41, 523–530 (2009).
Holland, W. L. et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J. Clin. Invest. 121, 1858–1870 (2011).
Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).
Koska, J. et al. A human model of dietary saturated fatty acid induced insulin resistance. Metabolism 65, 1621–1628 (2016).
Stephens, F. B. et al. Lipid-induced insulin resistance is associated with an impaired skeletal muscle protein synthetic response to amino acid ingestion in healthy young men. Diabetes 64, 1615–1620 (2015).
Lee, S., Boesch, C., Kuk, J. L. & Arslanian, S. Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African-American versus Caucasian adolescents. Metabolism 62, 417–423 (2013).
Imamura, F. et al. Effects of saturated fat, polyunsaturated fat, monounsaturated fat, and carbohydrate on glucose-insulin homeostasis: a systematic review and meta-analysis of randomised controlled feeding trials. PLoS Med. 13, e1002087 (2016).
Riserus, U., Willett, W. C. & Hu, F. B. Dietary fats and prevention of type 2 diabetes. Prog. Lipid Res. 48, 44–51 (2009). References 13 (meta-analysis) and 14 (review) report that SFA consumption is not associated with an increased risk of incident diabetes but that replacing dietary carbohydrates and SFAs with PUFAs is linked to improved glycaemia and insulin sensitivity.
Tao, C. et al. Short-term versus long-term effects of adipocyte toll-like receptor 4 activation on insulin resistance in male mice. Endocrinology 158, 1260–1270 (2017).
Zhang, Y. et al. TAK-242, a Toll-like receptor 4 antagonist, protects against aldosterone-induced cardiac and renal injury. PLoS ONE 10, e0142456 (2015).
Jia, L. et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 3878 (2014).
Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458, 1191–1195 (2009).
Schaeffler, A. et al. Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology 126, 233–245 (2009).
Wang, Y. et al. Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat. Commun. 8, 13997 (2017).
Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).
Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 1673–1677 (2001).
Gao, Z. et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J. Biol. Chem. 277, 48115–48121 (2002).
Rui, L. et al. Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J. Clin. Invest. 107, 181–189 (2001).
Copps, K. D. et al. Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab. 11, 84–92 (2010).
Copps, K. D. & White, M. F. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55, 2565–2582 (2012). References 25 and 26 show that, contrary to the results of cell-based experiments relating Ser307 phosphorylation of IRS1 to impaired insulin signalling, Ser307 in mice is a positive regulatory site that maintains proximal insulin signalling.
Frakes, A. E. & Dillin, A. The UPR(ER): sensor and coordinator of organismal homeostasis. Mol. Cell 66, 761–771 (2017).
Hotamisligil, G. S. & Davis, R. J. Cell signaling and stress responses. Cold Spring Harb. Perspect. Biol. 8, a006072 (2016).
Pierre, N. et al. Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. PLoS ONE 8, e65061 (2013).
Perry, B. D. et al. Palmitate-induced ER stress and inhibition of protein synthesis in cultured myotubes does not require Toll-like receptor 4. PLoS ONE 13, e0191313 (2018).
Robblee, M. M. et al. Saturated fatty acids engage an IRE1alpha-dependent pathway to activate the NLRP3 inflammasome in myeloid cells. Cell Rep. 14, 2611–2623 (2016).
Leamy, A. K., Egnatchik, R. A. & Young, J. D. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog. Lipid Res. 52, 165–174 (2013).
Ersoy, B. A., Maner-Smith, K. M., Li, Y., Alpertunga, I. & Cohen, D. E. Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress. J. Clin. Invest. 128, 141–156 (2018).
Holzer, R. G. et al. Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 147, 173–184 (2011).
Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).
Corpeleijn, E. et al. Improvements in glucose tolerance and insulin sensitivity after lifestyle intervention are related to changes in serum fatty acid profile and desaturase activities: the SLIM study. Diabetologia 49, 2392–2401 (2006).
Forouhi, N. G. et al. Association of plasma phospholipid n-3 and n-6 polyunsaturated fatty acids with type 2 diabetes: the EPIC-InterAct case-cohort study. PLoS Med. 13, e1002094 (2016).
Kurotani, K. et al. High levels of stearic acid, palmitoleic acid, and dihomo-gamma-linolenic acid and low levels of linoleic acid in serum cholesterol ester are associated with high insulin resistance. Nutr. Res. 32, 669–675.e3 (2012).
Pfeuffer, M. & Jaudszus, A. Pentadecanoic and heptadecanoic acids: multifaceted odd-chain fatty acids. Adv. Nutr. 7, 730–734 (2016).
Weitkunat, K. et al. Odd-chain fatty acids as a biomarker for dietary fiber intake: a novel pathway for endogenous production from propionate. Am. J. Clin. Nutr. 105, 1544–1551 (2017).
Lalia, A. Z. & Lanza, I. R. Insulin-sensitizing effects of omega-3 fatty acids: lost in translation? Nutrients 8, E329 (2016).
Oh, D. Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).
Storlien, L. H. et al. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 237, 885–888 (1987).
Bosch, J. et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med. 367, 309–318 (2012).
Li, X., Yu, Y. & Funk, C. D. Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4). FASEB J. 27, 4987–4997 (2013).
Liu, Y. et al. The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A(2) via GPR120 receptor to produce prostaglandin E(2) and plays an anti-inflammatory role in macrophages. Immunology 143, 81–95 (2014).
Bjursell, M. et al. The beneficial effects of n-3 polyunsaturated fatty acids on diet induced obesity and impaired glucose control do not require Gpr120. PLoS ONE 9, e114942 (2014).
Paerregaard, S. I. et al. FFAR4 (GPR120) signaling is not required for anti-inflammatory and insulin-sensitizing effects of omega-3 fatty acids. Mediators Inflamm. 2016, 1536047 (2016).
Serhan, C. N. et al. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J. Exp. Med. 192, 1197–1204 (2000).
Claria, J., Nguyen, B. T., Madenci, A. L., Ozaki, C. K. & Serhan, C. N. Diversity of lipid mediators in human adipose tissue depots. Am. J. Physiol. Cell Physiol. 304, C1141–C1149 (2013).
Neuhofer, A. et al. Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation. Diabetes 62, 1945–1956 (2013).
Gonzalez-Periz, A. et al. Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J. 23, 1946–1957 (2009).
Hellmann, J., Tang, Y., Kosuri, M., Bhatnagar, A. & Spite, M. Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice. FASEB J. 25, 2399–2407 (2011).
Titos, E. et al. Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. J. Immunol. 187, 5408–5418 (2011).
Chiang, N., Dalli, J., Colas, R. A. & Serhan, C. N. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J. Exp. Med. 212, 1203–1217 (2015).
Hsiao, H. M. et al. Resolvin D1 attenuates polyinosinic-polycytidylic acid-induced inflammatory signaling in human airway epithelial cells via TAK1. J. Immunol. 193, 4980–4987 (2014).
Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014).
Ohira, T. et al. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J. Biol. Chem. 285, 3451–3461 (2010).
Qian, F., Korat, A. A., Malik, V. & Hu, F. B. Metabolic effects of monounsaturated fatty acid-enriched diets compared with carbohydrate or polyunsaturated fatty acid-enriched diets in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Care 39, 1448–1457 (2016).
Schwingshackl, L. & Hoffmann, G. Monounsaturated fatty acids, olive oil and health status: a systematic review and meta-analysis of cohort studies. Lipids Health Dis. 13, 154 (2014).
Nowak, C. et al. Effect of insulin resistance on monounsaturated fatty acid levels: a multi-cohort non-targeted metabolomics and Mendelian randomization study. PLoS Genet. 12, e1006379 (2016).
Perdomo, L. et al. Protective role of oleic acid against cardiovascular insulin resistance and in the early and late cellular atherosclerotic process. Cardiovasc. Diabetol. 14, 75 (2015).
Finucane, O. M. et al. Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1beta secretion and insulin resistance despite obesity. Diabetes 64, 2116–2128 (2015).
Rodriguez de Fonseca, F. et al. An anorexic lipid mediator regulated by feeding. Nature 414, 209–212 (2001).
Schwartz, G. J. et al. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab. 8, 281–288 (2008).
Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).
Chan, K. L. et al. Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated protein kinase (AMPK). J. Biol. Chem. 290, 16979–16988 (2015).
Souza, C. O. et al. Palmitoleic acid (n-7) attenuates the immunometabolic disturbances caused by a high-fat diet independently of PPARalpha. Mediators Inflamm. 2014, 582197 (2014).
Mozaffarian, D. et al. Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Am. J. Clin. Nutr. 92, 1350–1358 (2010).
Nestel, P., Clifton, P. & Noakes, M. Effects of increasing dietary palmitoleic acid compared with palmitic and oleic acids on plasma lipids of hypercholesterolemic men. J. Lipid Res. 35, 656–662 (1994).
Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014). This study reports the discovery of a novel class of lipids, branched FAHFAs, and shows that FAHFAs have anti-diabetic and anti-inflammatory effects.
Ma, Y. et al. An in silico MS/MS library for automatic annotation of novel FAHFA lipids. J. Cheminform. 7, 53 (2015).
Kuda, O. et al. Docosahexaenoic acid-derived fatty acid esters of hydroxy fatty acids (FAHFAs) with anti-inflammatory properties. Diabetes 65, 2580–2590 (2016).
Syed, I. et al. Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab. 27, 419–427.e4 (2018).
Lee, J. et al. Branched fatty acid esters of hydroxy fatty acids (FAHFAs) protect against colitis by regulating gut innate and adaptive immune responses. J. Biol. Chem. 291, 22207–22217 (2016).
Parsons, W. H. et al. AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs. Nat. Chem. Biol. 12, 367–372 (2016).
Kolar, M. J. et al. Branched fatty acid esters of hydroxy fatty acids are preferred substrates of the MODY8 protein carboxyl ester lipase. Biochemistry 55, 4636–4641 (2016).
Raeder, H. et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat. Genet. 38, 54–62 (2006).
Nelson, A. T. et al. Stereochemistry of endogenous palmitic acid ester of 9-hydroxystearic acid and relevance of absolute configuration to regulation. J. Am. Chem. Soc. 139, 4943–4947 (2017).
Shulman, G. I. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl. J. Med. 371, 1131–1141 (2014). This is a comprehensive review on the roles of ectopic lipids, especially DAGs, in insulin resistance, dyslipidaemia and cardiometabolic disease.
Erion, D. M. & Shulman, G. I. Diacylglycerol-mediated insulin resistance. Nat. Med. 16, 400–402 (2010).
Samuel, V. T., Petersen, K. F. & Shulman, G. I. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375, 2267–2277 (2010).
Szendroedi, J. et al. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc. Natl Acad. Sci. USA 111, 9597–9602 (2014).
Yu, C. et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277, 50230–50236 (2002).
Kim, J. K. et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004).
Li, Y. et al. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J. Biol. Chem. 279, 45304–45307 (2004).
Petersen, M. C. et al. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J. Clin. Invest. 126, 4361–4371 (2016).
Finck, B. N. & Hall, A. M. Does diacylglycerol accumulation in fatty liver disease cause hepatic insulin resistance? Biomed. Res. Int. 2015, 104132 (2015). This review article discusses the controversies on the roles of DAGs in insulin resistance.
Samuel, V. T. et al. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest. 117, 739–745 (2007).
Ferris, H. A. & Kahn, C. R. Unraveling the paradox of selective insulin resistance in the liver: the brain-liver connection. Diabetes 65, 1481–1483 (2016).
Brown, J. M. et al. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. J. Lipid Res. 51, 3306–3315 (2010).
Turpin, S. M. et al. Adipose triacylglycerol lipase is a major regulator of hepatic lipid metabolism but not insulin sensitivity in mice. Diabetologia 54, 146–156 (2011).
Amati, F. et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes 60, 2588–2597 (2011).
Kishimoto, A., Takai, Y., Mori, T., Kikkawa, U. & Nishizuka, Y. Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover. J. Biol. Chem. 255, 2273–2276 (1980).
Hannun, Y. A. & Obeid, L. M. Sphingolipids and their metabolism in physiology and disease. Nat. Rev. Mol. Cell Biol. 19, 175–191 (2018).
Park, J. W., Park, W. J. & Futerman, A. H. Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim. Biophys. Acta 1841, 671–681 (2014).
Holland, W. L. et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17, 55–63 (2011).
Peraldi, P., Hotamisligil, G. S., Buurman, W. A., White, M. F. & Spiegelman, B. M. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J. Biol. Chem. 271, 13018–13022 (1996).
Chavez, J. A. & Summers, S. A. A ceramide-centric view of insulin resistance. Cell Metab. 15, 585–594 (2012).
Ussher, J. R. et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59, 2453–2464 (2010).
Deevska, G. M. et al. Acid sphingomyelinase deficiency prevents diet-induced hepatic triacylglycerol accumulation and hyperglycemia in mice. J. Biol. Chem. 284, 8359–8368 (2009).
Blouin, C. M. et al. Plasma membrane subdomain compartmentalization contributes to distinct mechanisms of ceramide action on insulin signaling. Diabetes 59, 600–610 (2010).
Chalfant, C. E. et al. Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J. Biol. Chem. 274, 20313–20317 (1999).
Bourbon, N. A., Sandirasegarane, L. & Kester, M. Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J. Biol. Chem. 277, 3286–3292 (2002).
Hajduch, E. et al. Targeting of PKCzeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. Biochem. J. 410, 369–379 (2008).
Powell, D. J., Hajduch, E., Kular, G. & Hundal, H. S. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol. Cell. Biol. 23, 7794–7808 (2003).
Petersen, M. C. & Shulman, G. I. Roles of diacylglycerols and ceramides in hepatic insulin resistance. Trends Pharmacol. Sci. 38, 649–665 (2017).
Merrill, A. H. Jr Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem. Rev. 111, 6387–6422 (2011).
Bergman, B. C. et al. Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans. Diabetologia 59, 785–798 (2016).
Chung, J. O., Koutsari, C., Blachnio-Zabielska, A. U., Hames, K. C. & Jensen, M. D. Intramyocellular ceramides: subcellular concentrations and fractional de novo synthesis in postabsorptive humans. Diabetes 66, 2082–2091 (2017).
Montgomery, M. K. et al. Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: a beneficial role for very long-chain sphingolipid species. Biochim. Biophys. Acta 1861, 1828–1839 (2016).
Raichur, S. et al. CerS2 haploinsufficiency inhibits beta-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695 (2014).
Turpin, S. M. et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20, 678–686 (2014).
Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–789 (1963).
Goodpaster, B. H. & Sparks, L. M. Metabolic flexibility in health and disease. Cell Metab. 25, 1027–1036 (2017). This comprehensive review discusses the mechanisms for insulin resistance induced by metabolic inflexibility in muscle and adipose tissue.
Kelley, D. E., Goodpaster, B., Wing, R. R. & Simoneau, J. A. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am. J. Physiol. 277, E1130–E1141 (1999).
Kelley, D. E. & Mandarino, L. J. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49, 677–683 (2000). References 116 and 117 show the evidence for and describe the concept of metabolic inflexibility in the development of insulin resistance.
Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).
Perry, R. J. et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160, 745–758 (2015). This study shows that adipose inflammation-stimulated lipolysis increases the influx of acetyl-CoA into the liver, which activates pyruvate carboxylase and promotes hepatic gluconeogenesis, leading to hyperglycaemia. This occurs in insulin-resistant states such as obesity and T2DM.
Zhang, H. H., Halbleib, M., Ahmad, F., Manganiello, V. C. & Greenberg, A. S. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 51, 2929–2935 (2002).
Grant, R. W. & Stephens, J. M. Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis. Am. J. Physiol. Endocrinol. Metab. 309, E205–E213 (2015).
Lee, S. A., Yuen, J. J., Jiang, H., Kahn, B. B. & Blaner, W. S. Adipocyte-specific overexpression of retinol-binding protein 4 causes hepatic steatosis in mice. Hepatology 64, 1534–1546 (2016).
Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005).
Morigny, P., Houssier, M., Mouisel, E. & Langin, D. Adipocyte lipolysis and insulin resistance. Biochimie 125, 259–266 (2016).
Aguer, C. et al. Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J. 29, 336–345 (2015).
Koves, T. R. et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7, 45–56 (2008). This paper provides evidence of increased incomplete β-oxidation of lipids in states of insulin resistance and obesity, resulting in the accumulation of acylcarnitines.
Muoio, D. M. & Neufer, P. D. Lipid-induced mitochondrial stress and insulin action in muscle. Cell Metab. 15, 595–605 (2012).
Muoio, D. M. et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab. 15, 764–777 (2012).
Liepinsh, E. et al. Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance. Pharmacol. Res. 113, 788–795 (2016).
Bene, J., Hadzsiev, K. & Melegh, B. Role of carnitine and its derivatives in the development and management of type 2 diabetes. Nutr. Diabetes 8, 8 (2018).
Nurjhan, N., Consoli, A. & Gerich, J. Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus. J. Clin. Invest. 89, 169–175 (1992).
Best, C. H. & Ridout, J. H. The effects of cholesterol and choline on liver fat. J. Physiol. 86, 343–352 (1936).
Li, Z. & Vance, D. E. Phosphatidylcholine and choline homeostasis. J. Lipid Res. 49, 1187–1194 (2008).
Raubenheimer, P. J., Nyirenda, M. J. & Walker, B. R. A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet. Diabetes 55, 2015–2020 (2006).
Meikle, P. J. & Summers, S. A. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat. Rev. Endocrinol. 13, 79–91 (2017).
van der Veen, J. N. et al. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim. Biophys. Acta 1859, 1558–1572 (2017).
Lee, J. M. et al. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature 474, 506–510 (2011).
Liu, S. et al. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550–554 (2013).
Rong, X. et al. LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab. 18, 685–697 (2013).
Singh, A. B. & Liu, J. Identification of hepatic lysophosphatidylcholine acyltransferase 3 as a novel target gene regulated by peroxisome proliferator-activated receptor delta. J. Biol. Chem. 292, 884–897 (2017).
Cash, J. G. & Hui, D. Y. Liver-specific overexpression of LPCAT3 reduces postprandial hyperglycemia and improves lipoprotein metabolic profile in mice. Nutr. Diabetes 6, e206 (2016).
Drazic, A., Myklebust, L. M., Ree, R. & Arnesen, T. The world of protein acetylation. Biochim. Biophys. Acta 1864, 1372–1401 (2016).
Menzies, K. J., Zhang, H., Katsyuba, E. & Auwerx, J. Protein acetylation in metabolism — metabolites and cofactors. Nat. Rev. Endocrinol. 12, 43–60 (2016).
Moussaieff, A. et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 21, 392–402 (2015).
Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014).
Donohoe, D. R. et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48, 612–626 (2012).
Cai, L., Sutter, B. M., Li, B. & Tu, B. P. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol. Cell 42, 426–437 (2011).
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).
Carrer, A. et al. Impact of a high-fat diet on tissue acyl-coA and histone acetylation levels. J. Biol. Chem. 292, 3312–3322 (2017).
Lerin, C. et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 3, 429–438 (2006).
Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434, 113–118 (2005).
Sakai, M. et al. The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch. Nat. Commun. 7, 13147 (2016).
Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008).
Park, J. M., Kim, T. H., Jo, S. H., Kim, M. Y. & Ahn, Y. H. Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity. Sci. Rep. 5, 17395 (2015).
Fang, S. et al. The p300 acetylase is critical for ligand-activated farnesoid X receptor (FXR) induction of SHP. J. Biol. Chem. 283, 35086–35095 (2008).
Kemper, J. K. et al. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab. 10, 392–404 (2009).
Ma, K., Saha, P. K., Chan, L. & Moore, D. D. Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116, 1102–1109 (2006).
Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).
Banks, A. S. et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 8, 333–341 (2008).
Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M. & Tschop, M. H. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl Acad. Sci. USA 105, 9793–9798 (2008).
Purushotham, A., Xu, Q. & Li, X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. FASEB J. 26, 656–667 (2012).
Xu, F. et al. Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/− mice: a role of lipid mobilization and inflammation. Endocrinology 151, 2504–2514 (2010).
Chalkiadaki, A. & Guarente, L. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab. 16, 180–188 (2012).
Gillum, M. P. et al. SirT1 regulates adipose tissue inflammation. Diabetes 60, 3235–3245 (2011).
White, A. T. et al. Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice. Diabetologia 56, 1629–1637 (2013).
White, A. T. et al. High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression. Am. J. Physiol. Endocrinol. Metab. 307, E764–772 (2014).
Qiang, L. et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppargamma. Cell 150, 620–632 (2012).
Li, Y. et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J. 25, 1664–1679 (2011).
Wang, R. H. et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J. Clin. Invest. 121, 4477–4490 (2011).
Daitoku, H. et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc. Natl Acad. Sci. USA 101, 10042–10047 (2004).
Matsuzaki, H. et al. Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc. Natl Acad. Sci. USA 102, 11278–11283 (2005).
Rodgers, J. T. & Puigserver, P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl Acad. Sci. USA 104, 12861–12866 (2007).
Hirschey, M. D. et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 44, 177–190 (2011).
Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447–14452 (2008).
Lombard, D. B. et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27, 8807–8814 (2007).
Lantier, L. et al. SIRT3 is crucial for maintaining skeletal muscle insulin action and protects against severe insulin resistance in high-fat-fed mice. Diabetes 64, 3081–3092 (2015).
Fernandez-Marcos, P. J. et al. Muscle or liver-specific Sirt3 deficiency induces hyperacetylation of mitochondrial proteins without affecting global metabolic homeostasis. Sci. Rep. 2, 425 (2012).
Hancock, C. R. et al. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc. Natl Acad. Sci. USA 105, 7815–7820 (2008).
Holloszy, J. O. “Deficiency” of mitochondria in muscle does not cause insulin resistance. Diabetes 62, 1036–1040 (2013). References 178 and 179 provide evidence that impaired mitochondrial function may not be a causative factor for insulin resistance.
Holloway, G. P., Bonen, A. & Spriet, L. L. Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals. Am. J. Clin. Nutr. 89, 455S–462S (2009).
Ryu, D. et al. A SIRT7-dependent acetylation switch of GABPbeta1 controls mitochondrial function. Cell Metab. 20, 856–869 (2014).
Shin, J. et al. SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep. 5, 654–665 (2013).
Yoshizawa, T. et al. SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. Cell Metab. 19, 712–721 (2014).
Canto, C., Menzies, K. J. & Auwerx, J. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22, 31–53 (2015).
Feng, D. et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011).
Sun, Z. et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 18, 934–942 (2012).
Hong, S. et al. Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat. Med. 23, 223–234 (2017).
Montgomery, R. L. et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J. Clin. Invest. 118, 3588–3597 (2008).
Sun, Z. et al. Diet-induced lethality due to deletion of the Hdac3 gene in heart and skeletal muscle. J. Biol. Chem. 286, 33301–33309 (2011).
Wang, S. et al. Insulin and mTOR pathway regulate HDAC3-mediated deacetylation and activation of PGK1. PLoS Biol. 13, e1002243 (2015).
Yang, X. & Qian, K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat. Rev. Mol. Cell Biol. 18, 452–465 (2017).
Hirschey, M. D. & Zhao, Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol. Cell Proteomics 14, 2308–2315 (2015).
Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E. & Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 15, 536–550 (2014).
Resh, M. D. Fatty acylation of proteins: the long and the short of it. Prog. Lipid Res. 63, 120–131 (2016).
Guan, X. & Fierke, C. A. Understanding protein palmitoylation: biological significance and enzymology. Sci. China Chem. 54, 1888–1897 (2011).
Yalovsky, S., Rodr Guez-Concepcion, M. & Gruissem, W. Lipid modifications of proteins - slipping in and out of membranes. Trends Plant Sci. 4, 439–445 (1999).
Ren, W., Jhala, U. S. & Du, K. Proteomic analysis of protein palmitoylation in adipocytes. Adipocyte 2, 17–28 (2013).
Du, K., Murakami, S., Sun, Y., Kilpatrick, C. L. & Luscher, B. DHHC7 palmitoylates glucose transporter 4 (Glut4) and regulates Glut4 membrane translocation. J. Biol. Chem. 292, 2979–2991 (2017).
Ren, W., Sun, Y. & Du, K. Glut4 palmitoylation at Cys223 plays a critical role in Glut4 membrane trafficking. Biochem. Biophys. Res. Commun. 460, 709–714 (2015).
Wei, X. et al. De novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation. J. Biol. Chem. 286, 2933–2945 (2011).
Spinelli, M. et al. Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a. Nat. Commun. 8, 2009 (2017).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18, 190–195 (2010).
Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013). References 202 and 204 provide evidence of altered gut microbiota in obesity and insulin resistance and show that this increases the propensity to develop obesity and insulin resistance.
Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916 e917 (2012).
Todesco, T., Rao, A. V., Bosello, O. & Jenkins, D. J. Propionate lowers blood glucose and alters lipid metabolism in healthy subjects. Am. J. Clin. Nutr. 54, 860–865 (1991).
Venter, C. S., Vorster, H. H. & Cummings, J. H. Effects of dietary propionate on carbohydrate and lipid metabolism in healthy volunteers. Am. J. Gastroenterol. 85, 549–553 (1990).
Chambers, E. S. et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64, 1744–1754 (2015).
De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).
den Besten, G. et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARgamma-dependent switch from lipogenesis to fat oxidation. Diabetes 64, 2398–2408 (2015).
Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).
Gao, Z. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58, 1509–1517 (2009).
Perry, R. J. et al. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).
Ang, Z. & Ding, J. L. GPR41 and GPR43 in obesity and inflammation — protective or causative? Front. Immunol. 7, 28 (2016).
Brown, A. J. et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 (2003).
Canfora, E. E., Jocken, J. W. & Blaak, E. E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577–591 (2015).
Karaki, S. et al. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J. Mol. Histol. 39, 135–142 (2008).
Thangaraju, M. et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69, 2826–2832 (2009).
Jiang, L. et al. Increased brain uptake and oxidation of acetate in heavy drinkers. J. Clin. Invest. 123, 1605–1614 (2013).
Al-Lahham, S. H. et al. Regulation of adipokine production in human adipose tissue by propionic acid. Eur. J. Clin. Invest. 40, 401–407 (2010).
Xiong, Y. et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc. Natl Acad. Sci. USA 101, 1045–1050 (2004).
Freeland, K. R. & Wolever, T. M. Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha. Br. J. Nutr. 103, 460–466 (2010).
Psichas, A. et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. (Lond.) 39, 424–429 (2015).
Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364–371 (2012).
Aberdein, N., Schweizer, M. & Ball, D. Sodium acetate decreases phosphorylation of hormone sensitive lipase in isoproterenol-stimulated 3T3-L1 mature adipocytes. Adipocyte 3, 121–125 (2014).
Ge, H. et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 149, 4519–4526 (2008).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451–455 (2013).
Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).
Al-Lahham, S. et al. Propionic acid affects immune status and metabolism in adipose tissue from overweight subjects. Eur. J. Clin. Invest. 42, 357–364 (2012).
Liu, T. et al. Short-chain fatty acids suppress lipopolysaccharide-induced production of nitric oxide and proinflammatory cytokines through inhibition of NF-kappaB pathway in RAW264.7 cells. Inflammation 35, 1676–1684 (2012).
Cox, M. A. et al. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J. Gastroenterol. 15, 5549–5557 (2009).
Li, G., Yao, W. & Jiang, H. Short-chain fatty acids enhance adipocyte differentiation in the stromal vascular fraction of porcine adipose tissue. J. Nutr. 144, 1887–1895 (2014).
Dewulf, E. M. et al. Evaluation of the relationship between GPR43 and adiposity in human. Nutr. Metab. 10, 11 (2013).
Hong, Y. H. et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146, 5092–5099 (2005).
Priyadarshini, M. et al. An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol. Endocrinol. 29, 1055–1066 (2015).
Felig, P., Marliss, E. & Cahill, G. F. Jr. Plasma amino acid levels and insulin secretion in obesity. N. Engl. J. Med. 281, 811–816 (1969).
Cheng, S. et al. Adipose tissue dysfunction and altered systemic amino acid metabolism are associated with non-alcoholic fatty liver disease. PLoS ONE 10, e0138889 (2015).
Iwasa, M. et al. Elevation of branched-chain amino acid levels in diabetes and NAFL and changes with antidiabetic drug treatment. Obes. Res. Clin. Pract. 9, 293–297 (2015).
Bhattacharya, S. et al. Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. Atherosclerosis 232, 191–196 (2014).
Shah, S. H. et al. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circ. Cardiovasc. Genet. 3, 207–214 (2010).
Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).
Wurtz, P. et al. Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults. Diabetes Care 36, 648–655 (2013).
Newgard, C. B. Metabolomics and metabolic diseases: where do we stand? Cell Metab. 25, 43–56 (2017). This comprehensive review discusses the emerging roles of metabolites, especially BCAAs, in insulin resistance.
Shah, S. H. & Newgard, C. B. Integrated metabolomics and genomics: systems approaches to biomarkers and mechanisms of cardiovascular disease. Circ. Cardiovasc. Genet. 8, 410–419 (2015).
Newgard, C. B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).
She, P. et al. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am. J. Physiol. Endocrinol. Metab. 293, E1552–E1563 (2007).
Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).
Lackey, D. E. et al. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am. J. Physiol. Endocrinol. Metab. 304, E1175–E1187 (2013).
Herman, M. A., She, P., Peroni, O. D., Lynch, C. J. & Kahn, B. B. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J. Biol. Chem. 285, 11348–11356 (2010).
Burrill, J. S. et al. Inflammation and ER stress regulate branched-chain amino acid uptake and metabolism in adipocytes. Mol. Endocrinol. 29, 411–420 (2015).
Zimmerman, H. A., Olson, K. C., Chen, G. & Lynch, C. J. Adipose transplant for inborn errors of branched chain amino acid metabolism in mice. Mol. Genet. Metab. 109, 345–353 (2013).
Shin, A. C. et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 20, 898–909 (2014).
Lefort, N. et al. Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes 59, 2444–2452 (2010).
White, P. J. et al. Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export. Mol. Metab. 5, 538–551 (2016).
Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381 (2016).
Lotta, L. A. et al. Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a Mendelian randomisation analysis. PLoS Med. 13, e1002179 (2016).
Smith, G. I. et al. Protein ingestion induces muscle insulin resistance independent of leucine-mediated mTOR activation. Diabetes 64, 1555–1563 (2015).
Macotela, Y. et al. Dietary leucine — an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS ONE 6, e21187 (2011).
Zeanandin, G. et al. Differential effect of long-term leucine supplementation on skeletal muscle and adipose tissue in old rats: an insulin signaling pathway approach. Age (Dordr) 34, 371–387 (2012).
Xiao, F. et al. Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice. Metabolism 63, 841–850 (2014).
Jang, C. et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat. Med. 22, 421–426 (2016).
Roberts, L. D. et al. beta-Aminoisobutyric acid induces browning of white fat and hepatic beta-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014).
Sun, H. et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133, 2038–2049 (2016).
Li, T. et al. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metab. 25, 374–385 (2017).
Green, C. R. et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12, 15–21 (2016).
Su, X. et al. Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: effects of obesity and weight loss. Obesity (Silver Spring) 23, 329–334 (2015).
Malloy, V. L. et al. Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell 5, 305–314 (2006).
Stone, K. P., Wanders, D., Orgeron, M., Cortez, C. C. & Gettys, T. W. Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice. Diabetes 63, 3721–3733 (2014).
Wanders, D. et al. UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. FASEB J. 29, 2603–2615 (2015).
Wanders, D. et al. FGF21 mediates the thermogenic and insulin-sensitizing effects of dietary methionine restriction but not its effects on hepatic lipid metabolism. Diabetes 66, 858–867 (2017).
Epner, D. E., Morrow, S., Wilcox, M. & Houghton, J. L. Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Nutr. Cancer 42, 158–166 (2002).
Stone, K. P. et al. Compromised responses to dietary methionine restriction in adipose tissue but not liver of ob/ob mice. Obesity (Silver Spring) 23, 1836–1844 (2015).
Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015).
Chen, T. et al. Tryptophan predicts the risk for future type 2 diabetes. PLoS ONE 11, e0162192 (2016).
Shah, S. H. et al. Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia 55, 321–330 (2012).
Laferrere, B. et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci. Transl Med. 3, 80re82 (2011).
Cotter, D. G. et al. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia. J. Clin. Invest. 124, 5175–5190 (2014).
Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).
Taggart, A. K. et al. D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652 (2005).
Kimura, I. et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl Acad. Sci. USA 108, 8030–8035 (2011).
Shimazu, T. et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
Goldberg, E. L. et al. beta-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep. 18, 2077–2087 (2017).
Youm, Y. H. et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).
Rheinheimer, J., de Souza, B. M., Cardoso, N. S., Bauer, A. C. & Crispim, D. Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review. Metabolism 74, 1–9 (2017).
Houstis, N., Rosen, E. D. & Lander, E. S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944–948 (2006).
Fisher, F. M. & Maratos-Flier, E. Understanding the physiology of FGF21. Annu. Rev. Physiol. 78, 223–241 (2016).
Foster, G. D. et al. A randomized trial of a low-carbohydrate diet for obesity. N. Engl. J. Med. 348, 2082–2090 (2003).
Chavez, A. O. et al. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 32, 1542–1546 (2009).
Fazeli, P. K. et al. FGF21 and the late adaptive response to starvation in humans. J. Clin. Invest. 125, 4601–4611 (2015).
Douris, N. et al. Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice. Mol. Metab. 6, 854–862 (2017).
Chavez-Talavera, O., Tailleux, A., Lefebvre, P. & Staels, B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152, 1679–1694.e3 (2017).
Preidis, G. A., Kim, K. H. & Moore, D. D. Nutrient-sensing nuclear receptors PPARalpha and FXR control liver energy balance. J. Clin. Invest. 127, 1193–1201 (2017).
Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003).
Maruyama, T. et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714–719 (2002).
Broeders, E. P. et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 22, 418–426 (2015).
Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006).
Somm, E. et al. beta-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue. JCI Insight 2, 91809 (2017).
Fujisaka, S. et al. Antibiotic effects on gut microbiota and metabolism are host dependent. J. Clin. Invest. 126, 4430–4443 (2016).
Kumar, D. P. et al. Activation of transmembrane bile acid receptor TGR5 modulates pancreatic islet alpha cells to promote glucose homeostasis. J. Biol. Chem. 291, 6626–6640 (2016).
Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).
Ding, L. et al. Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice. Hepatology 64, 760–773 (2016).
Weber, G. et al. Regulation of purine and pyrimidine metabolism by insulin and by resistance to tiazofurin. Adv. Enzyme Regul. 23, 81–99 (1985).
Pelley, J. W. (ed.) Purine, Pyrimidine, and Single Carbon Metabolism, (Elsevier, 2012).
Deng, Y. et al. An adipo-biliary-uridine axis that regulates energy homeostasis. Science 355, eaaf5375 (2017).
Yamamoto, T. et al. Relationship between plasma uridine and insulin resistance in patients with non-insulin-dependent diabetes mellitus. Nucleosides Nucleotides Nucleic Acids 29, 504–508 (2010).
Hamada, T. et al. Plasma levels of uridine correlate with blood pressure and indicators of myogenic purine degradation and insulin resistance in hypertensive patients. Circ. J. 71, 354–356 (2007).
Urasaki, Y., Pizzorno, G. & Le, T. T. Chronic uridine administration induces fatty liver and pre-diabetic conditions in mice. PLoS ONE 11, e0146994 (2016).
Krylova, I. B., Bulion, V. V., Selina, E. N., Mironova, G. D. & Sapronov, N. S. Effect of uridine on energy metabolism, LPO, and antioxidant system in the myocardium under conditions of acute coronary insufficiency. Bull. Exp. Biol. Med. 153, 644–646 (2012).
Le, T. T. et al. Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation. J. Lipid Res. 54, 1044–1057 (2013).
Hall, A. M. et al. Abrogating monoacylglycerol acyltransferase activity in liver improves glucose tolerance and hepatic insulin signaling in obese mice. Diabetes 63, 2284–2296 (2014).
Agarwal, A. K. et al. Mogat1 deletion does not ameliorate hepatic steatosis in lipodystrophic (Agpat2−/−) or obese (ob/ob) mice. J. Lipid Res. 57, 616–630 (2016).
Ryu, D. et al. Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance. Diabetes 60, 1072–1081 (2011).
Ryu, D. et al. TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1. Cell Metab. 9, 240–251 (2009).
Schweitzer, G. G. et al. Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice. J. Lipid Res. 56, 848–858 (2015).
Chibalin, A. V. et al. Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance. Cell 132, 375–386 (2008).
Zhang, C. et al. Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol. J. Biol. Chem. 290, 3519–3528 (2015).
Jornayvaz, F. R. et al. Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proc. Natl Acad. Sci. USA 108, 5748–5752 (2011).
Monetti, M. et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 6, 69–78 (2007).
Choi, C. S. et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J. Biol. Chem. 282, 22678–22688 (2007).
Aburasayn, H., Al Batran, R. & Ussher, J. R. Targeting ceramide metabolism in obesity. Am. J. Physiol. Endocrinol. Metab. 311, E423–435 (2016).
Fayyaz, S. et al. Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype. Diabetologia 57, 373–382 (2014).
Hu, W., Bielawski, J., Samad, F., Merrill, A. H. Jr & Cowart, L. A. Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activity. J. Lipid Res. 50, 1852–1862 (2009).
Kaiser, C. & James, S. R. Acetylation of insulin receptor substrate-1 is permissive for tyrosine phosphorylation. BMC Biol. 2, 23 (2004).
Cao, J. et al. Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity. Nat. Commun. 8, 131 (2017).
LaBarge, S., Migdal, C. & Schenk, S. Is acetylation a metabolic rheostat that regulates skeletal muscle insulin action? Mol. Cells 38, 297–303 (2015).
Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010).
Sundaresan, N. R. et al. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci. Signal 4, ra46 (2011).
Glidden, E. J. et al. Multiple site acetylation of Rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt protein. J. Biol. Chem. 287, 581–588 (2012).
Yu, J. et al. Regulation of serine-threonine kinase Akt activation by NAD+-dependent deacetylase SIRT7. Cell Rep. 18, 1229–1240 (2017).
Boutant, M. & Canto, C. SIRT1 metabolic actions: integrating recent advances from mouse models. Mol. Metab. 3, 5–18 (2014).