The role of fatty acids in insulin resistance

Lipids in Health and Disease

Mary Perry¹  Barry Sears¹ 

[1] Inflammation Research Foundation, 200 Corporate Place, Peabody 01960, MA, USA

关键词: Endotoxemia;    Muscle;    Liver;    Adipose tissue;    Hypothalamus;    Omega-3 fatty acids;    Palmitic acid;    Fatty acids;    Inflammation;    Insulin resistance;   

Others  :  1233337
DOI  :  10.1186/s12944-015-0123-1

 received in 2015-07-02, accepted in 2015-09-21,  发布年份 2015

【 摘 要 】

Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. The underlying cause of insulin appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. However, the molecular basis for insulin resistance can be quite different in various organs. This review deals with various types of inflammatory inputs mediated by fatty acids, which affect the extent of insulin resistance in various organs.

【 授权许可】

   
2015 Sears and Perry.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013; 339:172-177.
• [2]Zeyda M, Stulnig TM. Obesity, inflammation, and insulin resistance--a mini-review. Gerontology. 2009; 55(4):379-386.
• [3]de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008; 582(1):97-105.
• [4]Gregor MF, Hotamistigli GS. Inflammatory mechanisms in obesity. Ann Rev Immunol. 2011; 29:415-445.
• [5]Pederson TM, Kramer DL, Rondinone CM. Serine/threonine phosphorylation of IRS-1 triggers its degradation. Diabetes. 2001; 50(1):24-31.
• [6]Drazin B. Molecular mechanisms of insulin resistance. Diabetes. 2006; 55(7):2392-2397.
• [7]Markovic TP, Jenkins AB, Campbell LV, Furler SM, Kraegen EW, Chisholm DJ. The determinants of glycemic responses to diet restriction and weight loss in obesity and NIDDM. Diabetes Care. 1998; 21(5):687-694.
• [8]Pagano G, Cavallo-Perin P, Cassader M, Bruno A, Ozzello A, Masciola Dall’omo AM et al.. An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest. 1983; 72(5):1814-1820.
• [9]Donga E, van Dijk M, van Dijk JG, Biermasz NR, Lammers GJ, van Kralingen KW et al.. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010; 95(6):2963-2968.
• [10]Dali-Youcef N, Mecili M, Ricci R, Andres E. Metabolic inflammation: connecting obesity and insulin resistance. Ann Med. 2013; 45(3):242-253.
• [11]Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997; 389:610-614.
• [12]Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al.. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306(5695):457-461.
• [13]Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J et al.. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005; 11(2):183-190.
• [14]Ebstein W. Zur therapie des diabetes mellitus, insbesordere uber die anwendung des salicylsuaren natron bei demselben. Berliner Klinische Wochenschrift. 1876; 13:337-340.
• [15]Williamson RT, Lond MD. On treatment of glycosia and diabetes mellitus with sodium salicylate. Brit Med J. 1901; 1:760-762.
• [16]Reid J, Macdougall AI, Andrews MM. On efficacy of salicylate in treating diabetes. Br Med J. 1957; 2:1071-1074.
• [17]Hecht A, Goldner MF. Reappraisal of the hypoglycemic action of acetylsalicylate. Metabolism. 1959; 8:418-428.
• [18]Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE et al.. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002; 109(10):1321-1326.
• [19]Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2010; 152(6):346-357.
• [20]Taubes G. Insulin resistance. Prosperity’s plague. Science. 2009; 325(5938):256-260.
• [21]Glass CK, Olefsky JM. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metabol. 2012; 15(5):635-644.
• [22]Ussher JR, Koves TR, Cadete VJ, Zhang L, Jaswal JS, Swyrd SJ et al.. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes. 2010; 59(10):2453-2464.
• [23]Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO et al.. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012; 122(1):153-162.
• [24]Thaler JP, Schwartz MW. Inflammation and obesity pathogenesis: the hypothalamus heats up. Endocrinology. 2010; 151(9):4109-4115.
• [25]Velloso LA, Schwartz MW. Altered hypothalamic function in diet-induced obesity. Int J Obes. 2011; 35(12):1455-1465.
• [26]Yue JT, Lam TK. Lipid sensing and insulin resistance in the brain. Cell Metab. 2012; 15(5):646-655.
• [27]Youn JH. Fat sensing and metabolic syndrome. Rev Endocr Metab Disord. 2014; 15(4):263-275.
• [28]Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE et al.. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci. 2009; 29(2):359-370.
• [29]Oh DY, Olefsky JM. Omega 3 fatty acids and GPR120. Cell Metab. 2012; 15(5):564-565.
• [30]Cintra DE, Ropelle ER, Moraes JC, Pauli JR, Morari J, Souza CT et al.. Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS One. 2012; 7(1):e30571.
• [31]Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002; 51(2):271-275.
• [32]Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA et al.. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes. 2012; 61(6):1455-1462.
• [33]De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC et al.. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005; 146(10):4192-4199.
• [34]Tripathi YB, Pandey V. Obesity and endoplasmic reticulum (ER) stresses. Front Immunol. 2012; 3:240.
• [35]Thaler JP, Guyenet SJ, Dorfman MD, Wisse BE, Schwartz MW. Hypothalamic inflammation: marker or mechanism of obesity pathogenesis? Diabetes. 2013; 62(8):2629-2634.
• [36]Moraes JC, Coope A, Morari J, Cintra DE, Roman EA, Pauli JR et al.. High-fat diet induces apoptosis of hypothalamic neurons. PLoS One. 2009; 4(4):e5045.
• [37]Borg ML, Omran SF, Weir J, Meikle PJ, Watt MJ. Consumption of a high-fat diet, but not regular endurance exercise training, regulates hypothalamic lipid accumulation in mice. J Physiol. 2012; 590(Pt 17):4377-4389.
• [38]Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W et al.. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010; 142(5):687-698.
• [39]Vinolo MA, Hirabara SM, Curi R. G-protein-coupled receptors as fat sensors. Curr Opin Clin Nutr Metab Care. 2012; 15(2):112-116.
• [40]Auvinen HE, Romijn JA, Biermasz NR, Pijl H, Havekes LM, Smit JW et al.. The effects of high fat diet on the basal activity of the hypothalamus-pituitary-adrenal axis in mice. J Endocrinol. 2012; 214(2):191-197.
• [41]Serrano A, Pavon FJ, Tovar S, Casanueva F, Senaris R, Dieguez C et al.. Oleoylethanolamide: effects on hypothalamic transmitters and gut peptides regulating food intake. Neuropharmacology. 2011; 60(4):593-601.
• [42]Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008; 118(3):829-838.
• [43]Perrini S, Ficarella R, Picardi E, Cignarelli A, Barbaro M, Nigro P et al.. Differences in gene expression and cytokine release profiles highlight the heterogeneity of distinct subsets of adipose tissue-derived stem cells in the subcutaneous and visceral adipose tissue in humans. PLoS One. 2013; 8(3):e57892.
• [44]Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J et al.. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med. 2008; 168(15):1617-1624.
• [45]Lionetti L, Mollica MP, Lombardi A, Cavaliere G, Gifuni G, Barletta A. From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Nutr Metab Cardiovasc Dis. 2009; 19(2):146-152.
• [46]Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444(7121):860-867.
• [47]He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF-1(alpha) activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab. 2011; 300(5):E877-E885.
• [48]Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS. Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am J Physiol Gastrointest Liver Physiol. 2007; 293(1):G1-G4.
• [49]Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994; 91(11):4854-4858.
• [50]Zhang HH, Halbleib M, Ahmad F, Manganiello VC, Greenberg AS. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes. 2002; 51(10):2929-2935.
• [51]Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112(12):1796-1808.
• [52]Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al.. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112(12):1821-1830.
• [53]Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS et al.. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999; 4(4):611-617.
• [54]Ye J. Regulation of PPARgamma function by TNF-alpha. Biochem Biophys Res Commun. 2008; 374(3):405-408.
• [55]Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC et al.. EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism. Kidney Int. 2005; 67(3):867-874.
• [56]Scazzocchio B, Vari R, Filesi C, D’Archivio M, Santangelo C, Giovannini C et al.. Cyanidin-3-O-(sup)-glucoside and protocatechuic acid exert insulin-like effects by upregulating PPAR(sup) activity in human omental adipocytes. Diabetes. 2011; 60(9):2234-2244.
• [57]Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E et al.. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005; 46(11):2347-2355.
• [58]Kraemer FB, Takeda D, Natu V, Sztalryd C. Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways. Metabolism. 1998; 47(5):555-559.
• [59]Garfinkel AG, Nilsson-ehle P, Schotz MC. Regulation of lipoprotein lipase. Induction by insulin. Biochim Biophys Acta. 1976; 424(2):264-273.
• [60]Chabowski A, Coort SL, Calles-Escandon J, Tandon NN, Glatz JF, Luiken JJ et al.. Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm. Am J Physiol Endocrinol Metab. 2004; 287(4):E781-E789.
• [61]Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008; 7(6):489-503.
• [62]Jiao P, Ma J, Feng B, Zhang H, Diehl JA, Chin EA, et al. FFA-induced adipocyte inflammation and insulin resistance. Obesity. 2011;19(3):483–91.
• [63]Horowitz JF, Klein S. Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women. Am J Physiol Endocrinol Metab. 2000; 278(6):E1144-E1152.
• [64]Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. 2006; 45(1):42-72.
• [65]Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta. 2014; 1842(3):446-462.
• [66]Unger RH. Weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003; 144(12):5159-5165.
• [67]Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012; 148(5):852-871.
• [68]Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007; 30(3):734-743.
• [69]Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014; 510(7503):84-91.
• [70]German J, Kim F, Schwartz GJ, Havel PJ, Rhodes CJ, Schwartz MW et al.. Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology. 2009; 150(10):4502-4511.
• [71]Kraegen EW, Clark PW, Jenkins AB, Daley EA, Chisholm DJ, Storlien LH. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes. 1991; 40(11):1397-1403.
• [72]De Fronzo RA. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. Int J Clin Pract Suppl. 2004; 143:9-21.
• [73]Diraison F, Yankah V, Letexier D, Dusserre E, Jones P, Beylot M. Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans. J Lipid Res. 2003; 44(4):846-853.
• [74]Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW et al.. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009; 106(36):15430-15435.
• [75]Azuma K, Kadowaki T, Cetinel C, Kadota A, El-Saed A, Kadowaki S et al.. Higher liver fat content among Japanese in Japan compared with non-Hispanic whites in the United States. Metabolism. 2009; 58(8):1200-1207.
• [76]McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D et al.. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol. 2005; 96(3):399-404.
• [77]Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006; 116(7):1793-1801.
• [78]Pang S, Tang H, Zhuo S, Zang YQ, Le Y. Regulation of fasting fuel metabolism by toll-like receptor 4. Diabetes. 2010; 59(12):3041-3048.
• [79]Straczkowski M, Kowalska I, Nikolajuk A, Dzienis-Straczkowska S, Kinalska I, Baranowski M et al.. Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes. 2004; 53(5):1215-1221.
• [80]Adams JM, Pratipanawatr T, Berria R, Wang E, De Fronzo RA, Sullards MC et al.. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes. 2004; 53(1):25-31.
• [81]Turcotte LP, Fisher JS. Skeletal muscle insulin resistance. Phys Ther. 2008; 88(11):1279-1296.
• [82]German MS. Glucose sensing in pancreatic islet beta cells: the key role of glucokinase and the glycolytic intermediates. Proc Natl Acad Sci U S A. 1993; 90(5):1781-1785.
• [83]Wei D, Li J, Shen M, Jia W, Chen N, Chen T, Su D et al.. Cellular production of n-3 PUFAs and reduction of n-6-to-n-3 ratios in the pancreatic beta-cells and islets enhance insulin secretion and confer protection against cytokine-induced cell death. Diabetes. 2010; 59(2):471-478.
• [84]Duca FA, Yue JT. Fatty acid sensing in the gut and the hypothalamus. Mol Cell Endocrinol. 2014;397(1-2):22–33.
• [85]Schwartz GJ, Fu J, Astarita G, Li X, Gaetani S, Campolongo P et al.. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab. 2008; 8(4):281-288.
• [86]Martinez de Ubago M, Garcia-Oya I, Perez-Perez A, Canfran-Duque A, Quintana-Portillo R, Rodriguez de Fonseca F et al.. Oleoylethanolamide, a natural ligand for PPAR-alpha, inhibits insulin receptor signaling in HTC rat hepatoma cells. Biochim Biophys Acta. 2009; 1791(8):740-745.
• [87]Chaudhri OB, Field BC, Bloom SR. Gastrointestinal satiety signals. Int J Obes. 2008; 32 Suppl 7:S28-S31.
• [88]Field BC, Chaudhri OB, Bloom SR. Bowels control brain: gut hormones and obesity. Nat Rev Endocrinol. 2010; 6(8):444-453.
• [89]Owyang C, Logsdon CD. New insights into neurohormonal regulation of pancreatic secretion. Gastroenterology. 2004; 127(3):957-969.
• [90]Hayes MR, Covasa M. Dorsal hindbrain 5-HT3 receptors participate in control of meal size and mediate CCK-induced satiation. Brain Res. 2006; 1103(1):99-107.
• [91]Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E, Carvalho DP et al.. Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Endocrinology. 2011; 152(4):1314-1326.
• [92]Cheung GW, Kokorovic A, Lam CK, Chari M, Lam TK. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 2009; 10(2):99-109.
• [93]D’Alessio D. Intestinal hormones and regulation of satiety: the case for CCK, GLP-1, PYY, and Apo A-IV. JPEN J Parenter Enteral Nutr. 2008; 32(5):567-568.
• [94]Beglinger C, Degen L. Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY? Physiol Behav. 2006; 89(4):460-464.
• [95]le Roux CW, Batterham RL, Aylwin SJ, Patterson M, Borg CM, Wynne KJ et al.. Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology. 2006; 147(1):3-8.
• [96]Boey D, Lin S, Enriquez RF, Lee NJ, Slack K, Couzens M et al.. PYY transgenic mice are protected against diet-induced and genetic obesity. Neuropeptides. 2008; 42(1):19-30.
• [97]Morinigo R, Moize V, Musri M, Lacy AM, Navarro S, Marin JL et al.. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2006; 91(5):1735-1740.
• [98]Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006; 444:1022-1023.
• [99]Shen J, Obin MS, Zhao L. The gut microbiota, obesity and insulin resistance. Mol Aspects Med. 2013; 34(1):39-58.
• [100]Ding S, Chi MM, Scull BP, Rigby R, Schwerbrock NM, Magness S et al.. High-fat diet: bacterial interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One. 2010; 5(8):e12191.
• [101]Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012; 142(5):1100-1101.e2.
• [102]Amar J, Burcelin R, Ruidavets JB, Cani PD, Fauvel J, Alessi MC et al.. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr. 2008; 87(5):1219-1223.
• [103]Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM et al.. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care. 2009; 32(12):2281-2287.
• [104]Laugerette F, Furet JP, Debard C, Daira P, Loizon E, Geloen A et al.. Oil composition of high-fat diet affects metabolic inflammation differently in connection with endotoxin receptors in mice. Am J Physiol Endocrinol Metab. 2012; 302(3):E374-E386.
• [105]Ghoshal S, Witta J, Zhong J, de Villiers W, Eckhardt E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res. 2009; 50(1):90-97.
• [106]Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelia D et al.. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56(7):1761-1772.
• [107]Cani PD, Bibiloni R, Knauf C, Waget A, Neyrick AM, Delzenne NM et al.. Changes in gut microbiotia control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008; 57(6):1470-1481.
• [108]Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Backhed F. Crosstalk between gut microbriota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 2015; 22(10):1-11.