Adipocyte metabolism and obesity (2008)

Adipose tissue metabolism exerts a profound impact on whole-body metabolism. We review how fuel partitioning between adipocytes and other tissues affects insulin signaling pathways. We discuss the role of adipose tissue inflammation in adipocyte metabolism and whole-body insulin sensitivity. Finally, we mention the role of adipokines in autocrine and paracrine signaling. Adipose tissue metabolism exerts a profound impact on whole-body metabolism. We review how fuel partitioning between adipocytes and other tissues affects insulin signaling pathways. We discuss the role of adipose tissue inflammation in adipocyte metabolism and whole-body insulin sensitivity. Finally, we mention the role of adipokines in autocrine and paracrine signaling. Obesity is associated with changes in adipocyte gene expression spanning many pathways. These changes alter fuel partitioning between adipose tissue and other tissues. In addition, they alter the hormonal milieu by changing the relative expression of adipose hormones, adipokines. Finally, many metabolites act as signaling molecules; thus, their redistribution alters signaling pathways in adipose and other tissues. The role of inflammation in obesity has gained attention, beginning with the discovery that the macrophage content of adipose tissue in obese humans and rodents increases dramatically [reviewed in (1de Luca C. Olefsky J.M. Inflammation and insulin resistance.FEBS Lett. 2008; 582: 97-105Crossref PubMed Scopus (750) Google Scholar)]. Thus, in evaluating gene expression from adipose tissue, one has to consider the change in tissue composition and the role of macrophage-derived molecules in the alteration of adipocyte gene expression. In the context of overnutrition, most of the attention has been directed to dietary fat and carbohydrates. However, high-calorie diets are often associated with increased protein intake. Of particular interest in relation to extrahepatic tissues are the branched chain amino acids (BCAAs). BCAA levels are increased in the bloodstream of obese humans and in animal models of obesity [reviewed in (2She P. Horn C.Van Reid T. Hutson S.M. Cooney R.N. Lynch C.J. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism.Am. J. Physiol. Endocrinol. Metab. 2007; 293: E1552-E1563Crossref PubMed Scopus (340) Google Scholar)]. Owing to the absence of the mitochondrial branched chain amino transferase in the liver, BCAAs bypass the liver and are selectively metabolized in extraphepatic tissues. BCAAs modulate food intake through hypothalamic signaling and regulate leptin production in adipose tissue. The increase in BCAAs in obesity appears to be due in part to reduced expression of mitochondrial branched chain amino transferase in adipose tissue (2She P. Horn C.Van Reid T. Hutson S.M. Cooney R.N. Lynch C.J. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism.Am. J. Physiol. Endocrinol. Metab. 2007; 293: E1552-E1563Crossref PubMed Scopus (340) Google Scholar). Amino acid excess affects insulin signaling and glucose metabolism. This results in a direct stimulation of gluconeogenesis (3Krebs M. Brehm A. Krssak M. Anderwald C. Bernroider E. Nowotny P. Roth E. Chandramouli V. Landau B.R. Waldhausl W. al et Direct and indirect effects of amino acids on hepatic glucose metabolism in humans.Diabetologia. 2003; 46: 917-925Crossref PubMed Scopus (91) Google Scholar) and decreased glucose transport and glycogen synthesis in muscle (4Krebs M. Krssak M. Bernroider E. Anderwald C. Brehm A. Meyerspeer M. Nowotny P. Roth E. Waldhausl W. Roden M. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans.Diabetes. 2002; 51: 599-605Crossref PubMed Scopus (297) Google Scholar). Through their activation of the mTor/S6 kinase pathway, amino acids stimulate serine phosphorylation of IRS1 and blunt insulin signaling (5Tremblay F. Krebs M. Dombrowski L. Brehm A. Bernroider E. Roth E. Nowotny P. Waldhausl W. Marette A. Roden M. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability.Diabetes. 2005; 54: 2674-2684Crossref PubMed Scopus (278) Google Scholar). Although animals go through feeding/fasting cycles, the liver maintains a relatively constant fatty acid flux into triglyceride biosynthesis [reviewed in (6Blasiole D.A. Davis R.A. Attie A.D. The physiological and molecular regulation of lipoprotein assembly and secretion.Mol. Biosyst. 2007; 3: 608-619Crossref PubMed Scopus (89) Google Scholar)]. During fasting, the free fatty acid is derived from lipolysis of adipose tissue triglyceride, is transported to the liver, and is re-esterified to form hepatic triglyceride. With a lipogenic diet, the fatty acids are synthesized de novo in liver and adipose tissue. In a healthy animal, hepatocytes are able to maintain a rate of VLDL secretion sufficient to prevent the accumulation of excess triglyceride, a condition termed hepatic steatosis. Hepatic steatosis occurs in >20% of the US population, with some ethnic groups as high as 45% (7Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2907) Google Scholar). It is especially common in obese individuals. The heritability of hepatic steatosis is quite high, and a candidate susceptibility gene, PNPLA3, a gene expressed in liver and adipose tissue, has recently been identified in a genome-wide association study (8Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. Boerwinkle E. Cohen J.C. Hobbs H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2179) Google Scholar). Early microarray experiments indicated that genes involved in lipogenesis are downregulated in adipose tissue of obese leptin-deficient mice (9Nadler S.T. Stoehr J.P. Schueler K.L. Tanimoto G. Yandell B.S. Attie A.D. The expression of adipogenic genes is decreased in obesity and diabetes mellitus.Proc. Natl. Acad. Sci. USA. 2000; 97: 11371-11376Crossref PubMed Scopus (320) Google Scholar, 10Soukas A. Cohen P. Socci N.D. Friedman J.M. Leptin-specific patterns of gene expression in white adipose tissue.Genes Dev. 2000; 14: 963-980PubMed Google Scholar). This also includes the master regulator of these genes, Srebp1c. Conversely, these same genes are upregulated in the liver. Interestingly, a comparison hepatic gene expression in diabetes-resistant (C57BL/6) versus diabetes-susceptible (BTBR) leptin-deficient mice showed that only the nondiabetic strain exhibited the induction of lipogenic genes in the liver (9Nadler S.T. Stoehr J.P. Schueler K.L. Tanimoto G. Yandell B.S. Attie A.D. The expression of adipogenic genes is decreased in obesity and diabetes mellitus.Proc. Natl. Acad. Sci. USA. 2000; 97: 11371-11376Crossref PubMed Scopus (320) Google Scholar). In the livers of obese mice from a diabetes-susceptible strain, Srebp1c and its target genes were not upregulated. The same trend is seen for Pparg, a gene normally not expressed at a high level in the liver, but one that is induced in the liver of obese and lipodystrophic animals (9Nadler S.T. Stoehr J.P. Schueler K.L. Tanimoto G. Yandell B.S. Attie A.D. The expression of adipogenic genes is decreased in obesity and diabetes mellitus.Proc. Natl. Acad. Sci. USA. 2000; 97: 11371-11376Crossref PubMed Scopus (320) Google Scholar, 11Reitman M.L. Metabolic lessons from genetically lean mice.Annu. Rev. Nutr. 2002; 22: 459-482Crossref PubMed Scopus (62) Google Scholar). The hepatic steatosis phenotype is rescued by ablation of the hepatic Pparg gene (11Reitman M.L. Metabolic lessons from genetically lean mice.Annu. Rev. Nutr. 2002; 22: 459-482Crossref PubMed Scopus (62) Google Scholar). This creates an interesting dichotomy between hepatic steatosis and diabetes susceptibility; the diabetes-resistant mouse strain is more susceptible to hepatic steatosis. Similar results have been observed in mice with lipodystrophy when the lipodystrophy mutation is studied in C57BL/6 versus a diabetes-susceptible strain, FVB (11Reitman M.L. Metabolic lessons from genetically lean mice.Annu. Rev. Nutr. 2002; 22: 459-482Crossref PubMed Scopus (62) Google Scholar). In short, the relative expression level of at least two key transcription factors, Srepb1c and Pparg, in adipose tissue and liver, plays a role in fuel partitioning between the two tissues. There is reason to believe that several factors in adipose tissue locally have an impact on peroxisome proliferator-activated receptor γ (PPARγ) activity. Such factors include the cytoplasmic lipid binding protein aP2, whose absence leads to increased PPARγ activity (12Makowski L. Brittingham K.C. Reynolds J.M. Suttles J. Hotamisligil G.S. The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities.J. Biol. Chem. 2005; 280: 12888-12895Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar), as well as the adipokine adiponectin, whose overexpression in adipose tissue causes a net increase in the transcription of PPARγ targets (13Kim J.Y. Wall E.van de Laplante M. Azzara A. Trujillo M.E. Hofmann S.M. Schraw T. Durand J.L. Li H. Li G. al et Obesity-associated improvements in metabolic profile through expansion of adipose tissue.J. Clin. Invest. 2007; 117: 2621-2637Crossref PubMed Scopus (997) Google Scholar). The partitioning of lipids between adipose tissue and other tissues plays an important role in insulin signaling and cellular viability. Adipose tissue is specialized for triglyceride storage and has a very high capacity to accumulate triglycerides. Thus, the enhanced lipolysis and consequent free fatty acid flux from adipose tissue in obesity exposes other tissues to a substantial fatty acid burden (14Horowitz J.F. Klein S. Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women.Am. J. Physiol. Endocrinol. Metab. 2000; 278: E1144-E1152Crossref PubMed Google Scholar). These other tissues can accumulate triglycerides, and this is associated with cell pathology and insulin resistance. However, it is important to point out that current evidence argues against triglyceride itself being the culprit in these fatty-acid-mediated actions. Rather, strong evidence supports a role for diacylglycerol in the blunting of insulin signaling. Increased expression of diacylglycerol acyl transferase improves insulin sensitivity (15Monetti M. Levin M.C. Watt M.J. Sajan M.P. Marmor S. Hubbard B.K. Stevens R.D. Bain J.R. Newgard C.B. Farese R.V. al Sr., et Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver.Cell Metab. 2007; 6: 69-78Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar), whereas inhibition of diacylglycerol kinase suppresses insulin signaling (16Chibalin A.V. Leng Y. Vieira E. Krook A. Bjornholm M. Long Y.C. Kotova O. Zhong Z. Sakane F. Steiler T. al et Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance.Cell. 2008; 132: 375-386Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). A likely target for diacylglycerol action is protein kinase C-Θ (17Kim J.K. Fillmore J.J. Sunshine M.J. Albrecht B. Higashimori T. Kim D.W. Liu Z.X. Soos T.J. Cline G.W. al W.R. O'Brien, et PKC-theta knockout mice are protected from fat-induced insulin resistance.J. Clin. Invest. 2004; 114: 823-827Crossref PubMed Scopus (416) Google Scholar), which upon stimulation by diacylglycerol, phosphorylates serine residues on insulin receptor substrates, blunting the insulin signal (18Hotamisligil G.S. Peraldi P. Budavari A. Ellis R. White M.F. Spiegelman B.M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.Science. 1996; 271: 665-668Crossref PubMed Scopus (2189) Google Scholar). In addition to diacylglycerol, there is also strong evidence implicating ceramide in the modulation of insulin sensitivity. Ceramide is structurally analogous to diacylglycerol by having two fatty acid moieties attached to a backbone. Instead of glycerol, the backbone is serine, and instead of giving rise to glycerolipids, ceramide is an intermediate in sphingolipid synthesis. Like diacylglycerols, ceramides are signaling molecules. They activate protein phosphatase 2A, which dephosphorylates and thus inactivates Akt/PKB, a key arm of the insulin signaling pathway (19Summers S.A. Garza L.A. Zhou H. Birnbaum M.J. Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide.Mol. Cell. Biol. 1998; 18: 5457-5464Crossref PubMed Scopus (363) Google Scholar). In addition, ceramides inhibit the translocation of Akt/PKB to the plasma membrane (20Stratford S. Hoehn K.L. Liu F. Summers S.A. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B.J. Biol. Chem. 2004; 279: 36608-36615Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar). Leptin also plays a profound role in fuel partitioning. Diet-induced obesity simultaneously leads to increased leptin secretion and a blunting of the autocrine leptin signal in adipocytes. The leptin signal tends to be anti-adipogenic, a conclusion that emerged from the protection from obesity afforded to transgenic mice overexpressing the leptin b receptor in adipocytes (21Wang M.Y. Orci L. Ravazzola M. Unger R.H. Fat storage in adipocytes requires inactivation of leptin's paracrine activity: implications for treatment of human obesity.Proc. Natl. Acad. Sci. USA. 2005; 102: 18011-18016Crossref PubMed Scopus (131) Google Scholar). This illustrates the point that adipose tissue expansion during a positive energy balance (i.e., overeating) is an integral component of the maintenance of energy homeostasis. These mice are deficient in both adipocyte hypertrophy and hyperplasia, resulting in an inability to expand adipose tissue mass under these conditions. Functionally, the net result is comparable to states of partial or complete lipodystrophy; for example, excess triglycerides accumulate ectopically in tissues such as liver, muscle, and β-cells, where they contribute significantly toward the lipotoxic effects of lipids, as discussed above. On the other end of the spectrum, we find a recently described mouse obesity model that overexpresses the adipocyte-derived circulating factor adiponectin (13Kim J.Y. Wall E.van de Laplante M. Azzara A. Trujillo M.E. Hofmann S.M. Schraw T. Durand J.L. Li H. Li G. al et Obesity-associated improvements in metabolic profile through expansion of adipose tissue.J. Clin. Invest. 2007; 117: 2621-2637Crossref PubMed Scopus (997) Google Scholar). In the context of a challenge with the Leptinob/ob mutation, these mice retain adiponectin levels at concentrations found in a lean mouse. these the mice expand their adipose tissue mass quite the excess seen in the Leptinob/ob the Leptinob/ob mutation and the excess of adipose tissue, these mice have a metabolic profile and retain insulin a lipid and of a in adipose tissue increased of fat is with a reduced of Hepatic which is seen at high levels in the Leptinob/ob is This is an in which the accumulation of lipids is excess lipids are by storage in fat a insulin sensitivity is These results that adipose tissue can a and a role in a metabolic This quite in a fat study that a in which and fat into a or adipose Y. S. effects of fat on Metab. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). of fat into a in insulin sensitivity and a in plasma glucose and insulin the animals also a in leptin and adiponectin, that other factors a role in the metabolic into the not alter the metabolic there to be both and factors for these metabolic This the important as to the are that prevent adipose tissue from its physiological role as a triglyceride storage to the accumulation of lipids in tissues. an point of the gene that we are toward to fat during of these can be during of food On the other of a (i.e., excess adipose tissue significantly the to a Leptin is one of a to food intake and increase energy during of adipose tissue However, the is not very as of during of On the other the of adiponectin be a on which this adiponectin is an that free fatty acids into adipocytes for its during adipose tissue prevent expansion of fat However, this at the of accumulation of a of these excess lipids in other tissues. The increased of especially is well at this D. M. M. Obesity is associated with macrophage accumulation in adipose tissue.J. Clin. Invest. 2003; PubMed Scopus Google Scholar). The of can increased and which is associated with decreased insulin sensitivity transgenic overexpression of in adipose tissue H. S. Y. R. S. H. S. al et contributes to macrophage into adipose tissue, insulin and hepatic steatosis in Clin. Invest. PubMed Scopus Google Scholar) is and sufficient to increased of However, it is not under physiological increased macrophage and inflammation is the result of a signaling or the result of an increased of seen during tissue of its a of inflammation in adipose tissue, through or through of is associated with improvements in and insulin sensitivity. inflammatory pathways are the of insulin other in adipose tissue the of adipose tissue In addition, the inflammation is by the activation of the inflammatory transcription in the activation pathway J.L. Obesity a in adipose tissue macrophage Clin. Invest. 2007; 117: PubMed Scopus Google there be factors in adipose tissue that this in adipose tissue model that is by is that adipocyte hypertrophy and for increased and tissue these two the expansion of adipose which stimulate a of gene expression and also to the of to the adipose tissue. expression changes with this model have been observed in a comparison of versus of mice of a strain a R.A. L. J. T. C. J. in gene expression obesity in genetically Genet. PubMed Scopus Google Scholar). has been by and by the of adipose tissue with in genetically obese A. Y. S. S. Y. R. M. al et Adipose tissue in obesity and its impact on 2007; PubMed Scopus Google Scholar) or leptin-deficient J. Z. J. is a factor for inflammation and adiponectin in adipose tissue of and dietary obese J. Physiol. Endocrinol. 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Genetic and be to the of these in adipose tissue is a associated with adipose tissue or it a to with in the context of an increased content in adipose tissue. and the associated protein have been associated with cellular and cell in a of cell for metabolic homeostasis. This is for cell with a very The with its production of is to in the The rate of protein secretion from adipocytes is the role of the adipocyte as an cell is many of the adipokines that the fat cell have relatively but at high levels adiponectin, several factors, and This for the and assembly of some of these factors, which in some to form Thus, the an important role in the cellular of the adipocyte in the lean as well as in the obese pathways of the as the and the are and can be in the adipocyte [reviewed in M.F. 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