Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue
We previously reported that adenosine monophosphate-activated protein kinase (AMPK) activity is lower in adipose tissue of morbidly obese individuals who are insulin resistant than in comparably obese people who are insulin sensitive. However, the number of patients and parameters studied were small. Here, we compared abdominal subcutaneous, epiploic, and omental fat from 16 morbidly obese individuals classified as insulin sensitive or insulin resistant based on the homeostatic model assessment of insulin resistance. We confirmed that AMPK activity is diminished in the insulin resistant group. A custom PCR array revealed increases in mRNA levels of a wide variety of genes associated with inflammation and decreases in PGC-1α and Nampt in omental fat of the insulin resistant group. In contrast, subcutaneous abdominal fat of the same patients showed increases in PTP-1b, VEGFa, IFNγ, PAI-1, and NOS-2 not observed in omental fat. Only angiotensinogen and CD4+ mRNA levels were increased in both depots. Surprisingly, TNFα was only increased in epiploic fat, which otherwise showed very few changes. Protein carbonyl levels, a measure of oxidative stress, were increased in all depots. Thus, adipose tissues of markedly obese insulin resistant individuals uniformly show decreased AMPK activity and increased oxidative stress compared with insulin sensitive patients. However, most changes in gene expression appear to be depot-specific. We previously reported that adenosine monophosphate-activated protein kinase (AMPK) activity is lower in adipose tissue of morbidly obese individuals who are insulin resistant than in comparably obese people who are insulin sensitive. However, the number of patients and parameters studied were small. Here, we compared abdominal subcutaneous, epiploic, and omental fat from 16 morbidly obese individuals classified as insulin sensitive or insulin resistant based on the homeostatic model assessment of insulin resistance. We confirmed that AMPK activity is diminished in the insulin resistant group. A custom PCR array revealed increases in mRNA levels of a wide variety of genes associated with inflammation and decreases in PGC-1α and Nampt in omental fat of the insulin resistant group. In contrast, subcutaneous abdominal fat of the same patients showed increases in PTP-1b, VEGFa, IFNγ, PAI-1, and NOS-2 not observed in omental fat. Only angiotensinogen and CD4+ mRNA levels were increased in both depots. Surprisingly, TNFα was only increased in epiploic fat, which otherwise showed very few changes. Protein carbonyl levels, a measure of oxidative stress, were increased in all depots. Thus, adipose tissues of markedly obese insulin resistant individuals uniformly show decreased AMPK activity and increased oxidative stress compared with insulin sensitive patients. However, most changes in gene expression appear to be depot-specific. Obesity is a risk factor for disorders such as type 2 diabetes, atherosclerotic cardiovascular disease, nonalcoholic fatty liver disease, hypertension, certain cancers, and even dementia (1Klöting N. Fasshauer M. Dietrich A. Kovacs P. Schon M.R. Kern M. Sutumvoll M. Blüher M. Insulin-sensitive obesity.Am. J. Physiol. Endocrinol. Metab. 2010; 299: E506-E515Crossref PubMed Scopus (605) Google Scholar). Insulin resistance is thought to play a significant role in the pathogenesis of these disorders. However, not all obese individuals are insulin resistant (2Sims E.A. Are there persons who are obese, but metabolically healthy?.Metabolism. 2001; 50: 1499-1504Abstract Full Text PDF PubMed Scopus (364) Google Scholar, 3Reaven G. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals.Diab. Vasc. Dis. Res. 2005; 2: 105-112Crossref PubMed Scopus (111) Google Scholar). A subgroup of such patients has been shown to be insulin sensitive and to have lower levels of ectopic fat in liver and skeletal muscle and decreased intra-abdominal fat compared with their insulin resistant counterparts (4Stefan N. Kantartzis K. Machann J. Schick F. Thamer C. Rittig K. Balletshofer B. Machicao F. Fritsche A. Häring H.U. Identification and characterization of metabolically benign obesity in humans.Arch. Intern. Med. 2008; 168: 1609-1616Crossref PubMed Scopus (829) Google Scholar, 5Gauthier M.S. Ruderman N.B. Adipose tissue inflammation and insulin resistance: all obese humans are not created equal.Biochem. J. 2010; 430: e1-e4Crossref PubMed Scopus (25) Google Scholar). 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AMPK activity and isoform protein expression are similar in muscle of obese subjects with and without type 2 diabetes.Am. J. Physiol. Endocrinol. Metab. 2004; 286: E239-E244Crossref PubMed Scopus (83) Google Scholar) studies, and in visceral adipose tissue of centrally obese humans with Cushings syndrome, a disorder associated with insulin resistance (16Kola B. Christ-Crain M. Lolli F. Arnaldi G. Giacchetti G. Boscaro M. Grossman A.B. Korbontis M. Changes in adenosine 5′-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome.J. Clin. Endocrinol. Metab. 2008; 93: 4969-4973Crossref PubMed Scopus (66) Google Scholar). Obesity is also frequently associated with chronic low-grade inflammation, and a causal relationship between such inflammation and the development of insulin resistance has been described (17Wellen K.E. Hotamisligil G.S. Inflammation, stress, and diabetes.J. Clin. Invest. 2005; 115: 1111-1119Crossref PubMed Scopus (3225) Google Scholar). Likewise, increased inflammation has been found in adipose tissue of insulin resistant compared with insulin sensitive obese patients (1Klöting N. Fasshauer M. Dietrich A. Kovacs P. Schon M.R. Kern M. Sutumvoll M. Blüher M. Insulin-sensitive obesity.Am. J. Physiol. Endocrinol. Metab. 2010; 299: E506-E515Crossref PubMed Scopus (605) Google Scholar, 18Barbarroja N. Lopez-Pedrera R. Mayas M.D. Garcia-Fuentes E. Garrido-Sánchez L. Macías-González M. El Bekay R. Vidal-Puig A. Tinahones F.J. The obese healthy paradox: is inflammation the answer?.Biochem. J. 2010; 430: 141-149Crossref PubMed Scopus (143) Google Scholar), suggesting that it could be a key factor that distinguishes the observed in obese humans is an in oxidative Thus, obese individuals are reported to have levels of G. Dietrich M. M. B. 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Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans.Biochem. Biophys. Res. Commun. 2011; 404: 382-387Crossref PubMed Scopus (164) Google Scholar). The was the All were for and an to their were insulin resistant and insulin sensitive based on their A of was the as described model insulin resistance and from glucose and insulin in 1985; PubMed Scopus Google Scholar). All were on an of abdominal subcutaneous, epiploic adipose tissue from the of the and omental fat were the of The tissues were in and of the sensitive resistant are compared with insulin sensitive in a are compared with insulin sensitive patients. from fat was the lipid tissue of from were the PCR was to the mRNA levels of genes shown in and A were as the the most and was for were in All PCR were with a PCR The was the based K.J. of gene expression PCR and the 2001; PubMed Scopus Google gene expression in fat of insulin resistant sensitive the of in insulin resistant compared with insulin sensitive patients for are to the in which the in was in a the of in insulin resistant compared with insulin sensitive patients for are to the in which the in was were from subcutaneous, epiploic, and omental adipose tissue that been in with and were for The protein of the was the acid with as a of protein were of a and The were to a with in with for and with AMPK Nampt and were with the were and were with of The of protein was molecular mass Protein was with an protein oxidation to a measure of oxidative In of protein was with and to the The were and the with an A was in was and the with are as was for all The was or of was The of insulin sensitive and resistant patients are in The were similar with to and and insulin levels were in the insulin resistant patients. 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The role of AMP-activated protein kinase in Res. 2008; PubMed Scopus Google was that of AMPK isoform was in the insulin resistant in gene expression between the were in the and In epiploic fat, we found increased mRNA levels for and in the insulin resistant The changes in TNFα and were to epiploic fat, a similar in in subcutaneous fat and a in in omental fat. in the insulin sensitive the mRNA levels of and angiotensinogen were in epiploic and omental fat and were than in subcutaneous fat Nampt is a enzyme in and it the activity of the and other H. S. a of and 2006; PubMed Scopus Google Scholar). Nampt protein in omental fat of the insulin resistant in with the decreased expression of its mRNA in mRNA or protein not was in of the depots. Protein a of oxidative stress, was in all depots. A is shown in of that the insulin sensitive of was in both epiploic and omental than in abdominal subcutaneous fat a the insulin resistant patients levels of oxidative in all with the insulin sensitive found in the subcutaneous abdominal fat The of was to in adipose tissue that obese humans who are insulin sensitive from comparably obese individuals who are insulin were on abdominal subcutaneous, epiploic, and omental fat The key the levels of genes were in all of the insulin resistant the genes that were increased genes in and also showed changes in their expression and in contrast, increases in protein of oxidative and decreases in AMPK activity were observed in all of the insulin resistant patients. It has been that visceral and subcutaneous fat with to both and and visceral adipose their to the metabolic Rev. PubMed Scopus Google Scholar). omental fat to be sensitive to the action of J. C. P. for in between subcutaneous and omental fat Clin. Endocrinol. Metab. 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Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans.Biochem. Biophys. Res. Commun. 2011; 404: 382-387Crossref PubMed Scopus (164) Google Scholar). A similar was observed in omental fat, the was not significant We also found decreases in Nampt mRNA and protein in omental fat of insulin resistant patients Nampt has been as a and enzyme that increases and stress H. E. A. levels 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). the role of Nampt in resistance to oxidative stress and to A. M. S. F. C. F. F. is for development and resistance to 2008; PubMed Scopus Google Scholar), the Nampt expression found could have to the oxidative stress as as inflammation in omental fat of the insulin resistant patients. It has also been based on in skeletal that Nampt be AMPK and that such regulation could for the of AMPK to C. M. L. P. J. 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The and for their in the and and for its we are very to and the of for their and with the with AMP kinase body mass index homeostatic model assessment of insulin resistance