Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes
Open accessAbstract
Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin's ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.
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IL-6 from adipose tissue macrophages is released systemically to signal to hepatocytes.
“studies suggest that IL-6 from adipose tissue macrophages is released systemically to signal to hepatocytes 18”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [18]
The Results section on IL-6 infusion describes IL-6 produced locally by white-adipose-tissue macrophages as promoting adipose lipolysis, which then increases hepatic acetyl CoA and glucose production. Although the paper reports elevated plasma IL-6, it does not describe the proposed mechanism as IL-6 signaling directly to hepatocytes; it identifies adipose tissue as the IL-6 target. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn metabolic disease, pro-inflammatory cytokines such as interleukin-6 from adipose tissue macrophages circulate systemically and promote hepatocyte insulin resistance.
“In metabolic disease, pro-inflammatory cytokines such as interleukin (IL)-6 from adipose tissue macrophages circulate systemically and promote hepatocyte insulin resistance 18 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [18]
The Results sections report elevated plasma and white-adipose-tissue macrophage IL-6 in high-fat-fed rats and show that IL-6 promotes hepatic insulin resistance. They attribute the effect to increased adipose-tissue lipolysis and hepatic acetyl-CoA–driven glucose production, not a demonstrated direct effect on hepatocytes. The Discussion reports an association with hepatic insulin resistance in obese adolescents, but does not establish the same causal pathway in humans. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIL-6 promotes hepatic insulin resistance through IL-6/STAT3-induced inhibition of insulin receptor signaling.
“consistent with previous studies that indicate IL-6 promotes hepatic insulin resistance through IL-6/STAT3induced inhibition of insulin receptor signaling 18,45,46”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [18]
The Results section reports that IL-6 infusion increased hepatic glucose production and describes IL-6-induced hepatic insulin resistance in rats. But it attributes the effect to increased adipose-tissue lipolysis, hepatic acetyl-CoA, and pyruvate carboxylase activity—not to STAT3-mediated inhibition of insulin receptor signaling. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn contexts of chronically increased IL6 such as obesity or rheumatoid arthritis, IL6 has been shown to induce insulin resistance.
“In contexts of chronically increased IL6 such as obesity or rheumatoid arthritis, IL6 has been shown to induce insulin resistance (Castaneda et al., 2019; Kim et al., 2004; Perry et al., 2015).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Perry et al., 2015
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Cites
Macrophages, inflammation, and insulin resistance
Olefsky, J. M., & Glass, C. K. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135846 · Cited by 2,733 · see citing works
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294 · see citing works
Self-citationMitochondrial dysfunction in the elderly: possible role in insulin resistance
Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D. L., DiPietro, L., Cline, G. W., & Shulman, G. I. (2003) · Science · doi:10.1126/science.1082889 · Cited by 2,107 · see citing works
Self-citationSubcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-α,in Vivo1
Mohamed‐Ali, V., Goodrick, S., Rawesh, A., Katz, D. R., Miles, J. M., Yudkin, J. S., Klein, S., & Coppack, S. W. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4450 · Cited by 2,012 · see citing works
Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future
Kahn, S. E., Cooper, M. E., & Del Prato, S. (2014) · The Lancet · doi:10.1016/s0140-6736(13)62154-6 · Cited by 1,743 · see citing works
INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT*
Steele, R. D. (1959) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1959.tb44923.x · Cited by 1,680 · see citing works
Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase
Haemmerle, G., Lass, A., Zimmermann, R., Gorkiewicz, G., Meyer, C., Rozman, J., Heldmaier, G., Maier, R., Theussl, C., Eder, S., et al. (2006) · Science · doi:10.1126/science.1123965 · Cited by 1,375 · see citing works
Boyle, J. P., Thompson, T. J., Gregg, E. W., Barker, L. E., & Williamson, D. F. (2010) · Population Health Metrics · doi:10.1186/1478-7954-8-29 · Cited by 1,309 · see citing works
Pickup, J. C., Mattock, M. B., Chusney, G. D., & Burt, D. J. (1997) · Diabetologia · doi:10.1007/s001250050822 · Cited by 1,241 · see citing works
Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease
Shulman, G. I. (2014) · New England Journal of Medicine · doi:10.1056/nejmra1011035 · Cited by 1,126 · see citing works
Self-citationAssociation and Activation of Jak-Tyk Kinases by CNTF-LIF-OSM-IL-6 β Receptor Components
Stahl, N., Boulton, T. G., Farruggella, T., Ip, N. Y., Davis, S., Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Barbieri, G., Pellegrini, S., et al. (1994) · Science · doi:10.1126/science.8272873 · Cited by 979 · see citing works
Hypothalamic insulin signaling is required for inhibition of glucose production
Obici, S., Zhang, B. B., Karkanias, G., & Rossetti, L. (2002) · Nature Medicine · doi:10.1038/nm1202-798 · Cited by 904 · see citing works
Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.
Pilkis, S. J., & Granner, D. K. (1992) · Annual Review of Physiology · doi:10.1146/annurev.ph.54.030192.004321 · Cited by 865 · see citing works
Lütticken, C., Wegenka, U. M., Yuan, J., Buschmann, J., Schindler, C., Ziemiecki, A., Harpur, A. G., Wilks, A. F., Yasukawa, K., Taga, T., et al. (1994) · Science · doi:10.1126/science.8272872 · Cited by 814 · cited 1× · see citing works
“…HGP was associated with a 50% reduction in hepatic acetyl CoA concentrations within 10 min of the start of the insulin infusion as well as a 60% suppression of whole-body glycerol and palmitate turnover at steady state with no changes in plasma lactate, glucagon, or liver glycogen concentrations (”
BackgroundJNK Expression by Macrophages Promotes Obesity-Induced Insulin Resistance and Inflammation
Han, M. S., Jung, D. Y., Morel, C., Lakhani, S. A., Kim, J. K., Flavell, R. A., & Davis, R. J. (2012) · Science · doi:10.1126/science.1227568 · Cited by 635 · see citing works
Self-citationCellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro, N., Erion, D. M., Zhang, D., Kahn, M., Beddow, S. A., Chu, X., Still, C. D., Gerhard, G. S., Han, X., Dziura, J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113359108 · Cited by 585 · see citing works
Self-citationFernandez-Real, J.-M., Vayreda, M., Richart, C., Gutierrez, C., Broch, M., Vendrell, J., & Ricart, W. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.3.7305 · Cited by 567 · see citing works
Desnutrin/ATGL Is Regulated by AMPK and Is Required for a Brown Adipose Phenotype
Ahmadian, M., Abbott, M. J., Tang, T., Hudak, C. S. S., Kim, Y., Bruss, M. D., Hellerstein, M. K., Lee, H., Samuel, V. T., Shulman, G. I., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.05.002 · Cited by 526 · see citing works
Self-citationAdipose tissue macrophages: their role in adipose tissue remodeling
Suganami, T., & Ogawa, Y. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0210072 · Cited by 446 · see citing works
Guschin, D. Y., Rogers, N. C., Briscoe, J., Witthuhn, B. A., Watling, D., Horn, F., Pellegrini, S., Yasukawa, K., Heinrich, P. C., & Stark, G. R. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07128.x · Cited by 434 · see citing works
Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men
Petersen, K. F., Dufour, S., Feng, J., Befroy, D., Dziura, J., Man, C. D., Cobelli, C., & Shulman, G. I. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608537103 · Cited by 403 · see citing works
Self-citationInsulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1
Lu, M., Wan, M., Leavens, K. F., Chu, Q., Monks, B. R., Fernandez, S., Ahima, R. S., Ueki, K., Kahn, C. R., & Birnbaum, M. J. (2012) · Nature Medicine · doi:10.1038/nm.2686 · Cited by 396 · see citing works
Self-citationHill, J. W., Elias, C. F., Fukuda, M., Williams, K. W., Berglund, E. D., Holland, W. L., Cho, Y.-R., Chuang, J.-C., Xu, Y., Choi, M., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.002 · Cited by 391 · see citing works
KEECH, D. B., & Utter, M. F. (1963) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)67874-3 · Cited by 324 · see citing works
Cooperation between brain and islet in glucose homeostasis and diabetes
Schwartz, M. W., Seeley, R. J., Tschöp, M. H., Woods, S. C., Morton, G. J., Myers, M. G., & D’Alessio, D. A. (2013) · Nature · doi:10.1038/nature12709 · Cited by 315 · see citing works
Adipose tissue as an endocrine organ: from theory to practice
Fonseca‐Alaniz, M. H., Takada, J., Alonso‐Vale, M. I. C., & Lima, F. B. (2007) · Jornal de Pediatria · doi:10.2223/jped.1709 · Cited by 299 · see citing works
Rebrin, K., Steil, G. M., Mittelman, S. D., & Bergman, R. N. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118846 · Cited by 288 · see citing works
Mechanisms of Insulin Resistance in Humans and Possible Links With Inflammation
Savage, D. B., Petersen, K. F., & Shulman, G. I. (2005) · Hypertension · doi:10.1161/01.hyp.0000163475.04421.e4 · Cited by 284 · see citing works
Self-citationCGI-58 Interacts with Perilipin and Is Localized to Lipid Droplets
Yamaguchi, T., Omatsu, N., Matsushita, S., & Osumi, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403920200 · Cited by 258 · see citing works
Perry, R. J., Kim, T.-H., Zhang, X., Lee, H., Pesta, D. H., Popov, V., Zhang, D., Rahimi, Y., Jurczak, M. J., Cline, G. W., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.004 · Cited by 230 · see citing works
Self-citationA method for the extraction of glycogen and metabolites from a single muscle sample
Dalrymple, R. H., & Hamm, R. (1973) · International Journal of Food Science & Technology · doi:10.1111/j.1365-2621.1973.tb01730.x · Cited by 224 · see citing works
Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle
Glund, S., Deshmukh, A., Long, Y. C., Moller, T., Koistinen, H. A., Caidahl, K., Zierath, J. R., & Krook, A. (2007) · Diabetes · doi:10.2337/db06-1733 · Cited by 219 · see citing works
ACCELERATION OF RENAL GLUCONEOGENESIS BY KETONE BODIES AND FATTY ACIDS
Krebs, H., Speake, R. N., & Hems, R. (1965) · Biochemical Journal · doi:10.1042/bj0940712 · Cited by 195 · see citing works
Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis
Perry, R. J., Zhang, X., Zhang, D., Kumashiro, N., Camporez, J. P., Cline, G. W., Rothman, D. L., & Shulman, G. I. (2014) · Nature Medicine · doi:10.1038/nm.3579 · Cited by 193 · see citing works
Self-citationHaeusler, R. A., Hartil, K., Vaitheesvaran, B., Arrieta‐Cruz, I., Knight, C. M., Cook, J. R., Kammoun, H. L., Febbraio, M. A., Juárez, R. G., Kurland, I. J., et al. (2014) · Nature Communications · doi:10.1038/ncomms6190 · Cited by 192 · see citing works
O tecido adiposo como órgão endócrino: da teoria à prática
Fonseca‐Alaniz, M. H., Takada, J., Alonso‐Vale, M. I. C., & Lima, F. B. (2007) · Jornal de Pediatria · doi:10.1590/s0021-75572007000700011 · Cited by 192 · see citing works
Straub, R. H., Hense, H. W., Andus, T., Schölmerich, J., Riegger, G. A. J., & Schunkert, H. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.3.6355 · Cited by 170 · see citing works
Yamaguchi, T., Omatsu, N., Emi, M., Nakashima, H., Ueno, K., Tanaka, T., Satouchi, K., Hirose, F., & Osumi, T. (2007) · Journal of Lipid Research · doi:10.1194/jlr.m600493-jlr200 · Cited by 168 · see citing works
Steptoe, A., Hackett, R. A., Lazzarino, A. I., Bostock, S., La Marca, R., Carvalho, L. A., & Hamer, M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1410401111 · Cited by 167 · see citing works
Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis
Jordan, S. D., Könner, A. C., & Brüning, J. C. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0414-7 · Cited by 163 · see citing works
Glucose dysregulation and hepatic steatosis in obese adolescents
Cali, A. M. G., de Oliveira, A. M., Kim, H.-J., Chen, S., Reyes‐Múgica, M., Escalera, S., Dziura, J., Taksali, S. E., Kursawe, R., Shaw, M. M., et al. (2009) · Hepatology · doi:10.1002/hep.22858 · Cited by 163 · see citing works
Self-citationKado, S., Nagase, T., & Nagata, N. (1999) · Acta Diabetologica · doi:10.1007/s005920050147 · Cited by 158 · see citing works
Lin, H. V., Plum, L., Ono, H., Juárez, R. G., Shanabrough, M., Borók, E., Horváth, T. L., Rossetti, L., & Accili, D. (2009) · Diabetes · doi:10.2337/db09-1303 · Cited by 152 · see citing works
Jurczak, M. J., Lee, A., Jornayvaz, F. R., Lee, H., Birkenfeld, A. L., Guigni, B. A., Kahn, M., Samuel, V. T., Glimcher, L. H., & Shulman, G. I. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.316760 · Cited by 142 · see citing works
Self-citationKursawe, R., Eszlinger, M., Narayan, D., Liu, T., Bazuine, M., Cali, A. M. G., D’Adamo, E., Shaw, M. M., Pierpont, B. M., Shulman, G. I., et al. (2010) · Diabetes · doi:10.2337/db10-0113 · Cited by 129 · see citing works
Self-citationLewis, G. F., Zinman, B., Groenewoud, Y., Vranić, M., & Giacca, A. (1996) · Diabetes · doi:10.2337/diab.45.4.454 · Cited by 119 · see citing works
Inflammasomes and Metabolic Disorders: Old Genes in Modern Diseases
Robbins, G. R., Wen, H., & Ting, J. P. ‐. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.03.029 · Cited by 114 · see citing works
Vatner, D. F., Weismann, D., Beddow, S. A., Kumashiro, N., Erion, D. M., Liao, X.-H., Grover, G. J., Webb, P., Phillips, K. J., Weiss, R. E., et al. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00573.2012 · Cited by 110 · see citing works
Self-citationEffects of Insulin on the Metabolic Control of Hepatic Gluconeogenesis In Vivo
Edgerton, D. S., Ramnanan, C. J., Grueter, C. A., Johnson, K., Lautz, M., Neal, D. W., Williams, P. E., & Cherrington, A. D. (2009) · Diabetes · doi:10.2337/db09-0328 · Cited by 91 · see citing works
Cernkovich, E. R., Deng, J., Bond, M. C., Combs, T. P., & Harp, J. B. (2008) · Endocrinology · doi:10.1210/en.2007-1148 · Cited by 87 · see citing works
Growth hormone reduces glucose transport but not GLUT-1 or GLUT-4 in adult and old rats
Cartee, G. D., & Bohn, E. E. (1995) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1995.268.5.e902 · Cited by 85 · see citing works
Yuen, D. Y. C., Dwyer, R. M., Matthews, V. B., Zhang, L., Drew, B. G., Neill, B., Kingwell, B. A., Clark, M. G., Rattigan, S., & Febbraio, M. A. (2009) · Diabetes · doi:10.2337/db08-0775 · Cited by 55 · see citing works
A critical evaluation of mass isotopomer distribution analysis of gluconeogenesis in vivo
Previs, S. F., Cline, G. W., & Shulman, G. I. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.1.e154 · Cited by 52 · see citing works
Self-citationThe regulation of yeast pyruvate carboxylase by acetyl-coenzyme A and l-aspartate
Cazzulo, J. J., & Stoppani, A. O. M. (1968) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(68)90263-4 · Cited by 50 · see citing works
Determination of the 13C-Labeling Pattern of Glutamate by Gas Chromatography-Mass Spectrometry
Beylot, M., David, F., & Brunengraber, H. (1993) · Analytical Biochemistry · doi:10.1006/abio.1993.1364 · Cited by 40 · see citing works
Studies on the mechanism of insulin action: Basic concepts and clinical implications
Hepp, K. D. (1977) · Diabetologia · doi:10.1007/bf01219697 · Cited by 39 · see citing works
Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation
Manteiga, S., Choi, K., Jayaraman, A., & Lee, K. (2013) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1213 · Cited by 36 · see citing works
The participation of acetyl-CoA in pyruvate carboxylase
Cooper, T., & Benedict, C. R. (1966) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(66)90479-7 · Cited by 31 · see citing works
Apparent co-operative effect of acetyl-CoA on sheep kidney pyruvate carboxylase
Barritt, G. J., KEECH, D. B., & Ai-Mee-Ling (1966) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(66)90186-0 · Cited by 29 · see citing works
Chisholm, A. B., Allan, E. H., & Titheradge, M. A. (1983) · Biochemical Journal · doi:10.1042/bj2140451 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028 · see citing works
Self-citationDeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611 · see citing works
Self-citationMechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002 · see citing works
Self-citationThe pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484 · see citing works
Self-citationThe integrative biology of type 2 diabetes
Roden, M., & Shulman, G. I. (2019) · Nature · doi:10.1038/s41586-019-1797-8 · Cited by 1,167 · see citing works
Self-citationTilg, H., Moschen, A. R., & Roden, M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.147 · Cited by 1,002 · see citing works
Cellular and Molecular Mechanisms of Metformin Action
LaMoia, T. E., & Shulman, G. I. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa023 · Cited by 791 · see citing works
Self-citationNonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745 · see citing works
Self-citationImpaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A., & Smith, U. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2017 · Cited by 462 · see citing works
Reassessing human adipose tissue
Cypess, A. M. (2022) · New England Journal of Medicine · doi:10.1056/nejmra2032804 · Cited by 404 · see citing works
Roles of diacylglycerols and ceramides in hepatic insulin resistance
Petersen, M. C., & Shulman, G. I. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.04.004 · Cited by 373 · see citing works
Self-citationRegulation of Adipose Tissue Inflammation by Interleukin 6
Han, M. S., White, A., Perry, R. J., Camporez, J.-P., Hidalgo, J., Shulman, G. I., & Davis, R. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920004117 · Cited by 344 · see citing works
Sergi, D., Naumovski, N., Heilbronn, L. K., Abeywardena, M., O’Callaghan, N., Lionetti, L., & Luscombe-Marsh, N. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00532 · Cited by 347 · see citing works
“Long-chain saturated fatty acids have been widely described as detrimental to metabolic health by promoting both metabolic inflammation and lipotoxicity (Summers, 2006; Sears and Perry, 2015; Sergi et al., 2018a,b).”
BackgroundResolving the paradox of hepatic insulin resistance
Santoleri, D., & Titchenell, P. M. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.10.016 · Cited by 336 · see citing works
Origin and function of stress-induced IL-6 in murine models
Qing, H., Desrouleaux, R., Israni-Winger, K., Mineur, Y. S., Fogelman, N., Zhang, C., Rashed, S., Palm, N. W., Sinha, R., Picciotto, M. R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.054 · Cited by 303 · see citing works
Self-citationBo, T., Gao, L., Yao, Z., Shao, S., Wang, X., Proud, C. G., & Zhao, J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.04.006 · Cited by 293 · see citing works
Inter-organ crosstalk during development and progression of type 2 diabetes mellitus
Xourafa, G., Korbmacher, M., & Roden, M. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00898-1 · Cited by 274 · see citing works
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Kim, M.-S., Krawczyk, S. A., Doridot, L., Fowler, A. J., Wang, J. X., Trauger, S. A., Noh, H.-L., Kang, H. J., Meissen, J. K., Blatnik, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81993 · Cited by 212 · see citing works
Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms
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Galsgaard, K. D., Pedersen, J., Knop, F. K., Holst, J. J., & Wewer Albrechtsen, N. J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00413 · Cited by 218 · see citing works
Stromsdorfer, K. L., Yamaguchi, S., Yoon, M. J., Moseley, A. C., Franczyk, M. P., Kelly, S. C., Qi, N., Imai, S.-I., & Yoshino, J. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.027 · Cited by 213 · see citing works
Ins and outs of the TCA cycle: the central role of anaplerosis
Inigo, M., Deja, S., & Burgess, S. C. (2021) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-120420-025558 · Cited by 189 · see citing works
A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
Maida, A., Zota, A., Sjøberg, K. A., Schumacher, J., Sijmonsma, T. P., Pfenninger, A., Christensen, M. M., Gantert, T., Fuhrmeister, J., Rothermel, U., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85946 · Cited by 170 · see citing works
Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance
Fazakerley, D. J., Chaudhuri, R., Yang, P., Maghzal, G. J., Thomas, K. C., Krycer, J. R., Humphrey, S. J., Parker, B. L., Fisher-Wellman, K. H., Meoli, C. C., et al. (2018) · eLife · doi:10.7554/elife.32111 · Cited by 160 · see citing works
Alkhouri, N., Lawitz, E., Noureddin, M., DeFronzo, R., & Shulman, G. I. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1668374 · Cited by 162 · see citing works
Self-citationMechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver
Jelenik, T., Kaul, K., Séquaris, G., Flögel, U., Phielix, E., Kotzka, J., Knebel, B., Fahlbusch, P., Hörbelt, T., Lehr, S., et al. (2017) · Diabetes · doi:10.2337/db16-1147 · Cited by 154 · see citing works
Self-citationNew insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
Honka, M.-J., Latva-Rasku, A., Bucci, M., Virtanen, K. A., Hannukainen, J. C., Kalliokoski, K. K., & Nuutila, P. (2018) · European Journal of Endocrinology · doi:10.1530/eje-17-0882 · Cited by 140 · see citing works
Hepatic glucose metabolism in the steatotic liver
Scoditti, E., Sabatini, S., Carli, F., & Gastaldelli, A. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00888-8 · Cited by 134 · see citing works
Stout, M. B., Steyn, F. J., Jurczak, M. J., Camporez, J.-P. G., Zhu, Y., Hawse, J. R., Jurk, D., Palmer, A. K., Xu, M., Pirtskhalava, T., et al. (2017) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glv309 · Cited by 119 · see citing works
Self-citationExercise, heat shock proteins and insulin resistance
Archer, A. E., Von Schulze, A. T., & Geiger, P. C. (2018) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2016.0529 · Cited by 122 · see citing works
Savage, T. M., Fortson, K. T., de los Santos-Alexis, K., Oliveras-Alsina, A., Rouanne, M., Rae, S. S., Gamarra, J. R., Shayya, H., Kornberg, A., Cavero, R., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.01.009 · Cited by 115 · see citing works
Inactivating hepatic follistatin alleviates hyperglycemia
Tao, R., Wang, C., Stöhr, O., Qiu, W., Hu, Y., Miao, J., Dong, X. C., Leng, S., Stefater, M., Stylopoulos, N., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0048-0 · Cited by 104 · see citing works
Sandforth, A., von Schwartzenberg, R. J., Arreola, E. V., Hanson, R. L., Sancar, G., Katzenstein, S., Lange, K., Preißl, H., Dreher, S. I., Weigert, C., et al. (2023) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(23)00235-8 · Cited by 100 · see citing works
Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease
ter Horst, K. W., Vatner, D. F., Zhang, D., Cline, G. W., Ackermans, M. T., Nederveen, A. J., Verheij, J., Demirkiran, A., van Wagensveld, B. A., Dallinga-Thie, G. M., et al. (2021) · Diabetes Care · doi:10.2337/dc20-1644 · Cited by 88 · see citing works
Self-citationChen, M., Guo, W.-L., Li, Q.-Y., Xu, J.-X., Cao, Y.-J., Liu, B., Yu, X.-D., Rao, P.-F., Ni, L., & Lv, X.-C. (2020) · Food & Function · doi:10.1039/c9fo03003d · Cited by 77 · see citing works
Camporez, J. P., Lyu, K., Goldberg, E. L., Zhang, D., Cline, G. W., Jurczak, M. J., Dixit, V. D., Petersen, K. F., & Shulman, G. I. (2019) · The Journal of Physiology · doi:10.1113/jp277270 · Cited by 71 · see citing works
Self-citationHolm, J. B., Rønnevik, A., Tastesen, H. S., Fjære, E., Fauske, K. R., Liisberg, U., Madsen, L., Kristiansen, K., & Liaset, B. (2016) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.12.017 · Cited by 45 · see citing works
A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21
Han, M. S., Perry, R. J., Camporez, J.-P., Scherer, P. E., Shulman, G. I., Gao, G., & Davis, R. J. (2021) · Genes & Development · doi:10.1101/gad.344556.120 · Cited by 43 · see citing works
Self-citationDesjardins, E. M., Wu, J., Lavoie, D. C. T., Ahmadi, E., Townsend, L. K., Morrow, M. R., Wang, D., Tsakiridis, E. E., Batchuluun, B., Fayyazi, R., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101193 · Cited by 33 · see citing works
Santos, H. O., & Penha-Silva, N. (2025) · Nutrition · doi:10.1016/j.nut.2024.112617 · Cited by 11 · see citing works
- Authors
- Perry, R. J., Camporez, J.-P. G., Kursawe, R., Titchenell, P. M., Zhang, D., Perry, C. J., Jurczak, M. J., Abudukadier, A., Han, M. S., Zhang, X.-M., Ruan, H.-B., Yang, X., Caprio, S., Kaech, S. M., Sul, H. S., Birnbaum, M. J., Davis, R. J., Cline, G. W., Petersen, K. F., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Yale University (US)
- University of Pennsylvania (US)
- University of Massachusetts Chan Medical School (US)
- University of California, Berkeley (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 4
- Pages
- 745-758
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4498261
- OpenAlex
- W2031533316
- Cited by
- 719
- References
- 60
- Citations by year
- 2026: 45 · 2025: 41 · 2024: 59 · 2023: 55 · 2022: 65 · 2021: 75 · 2020: 86 · 2019: 65 · 2018: 66 · 2017: 81 · 2016: 56 · 2015: 23
- FWCI
- 59.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Novo Nordisk Foundation Center for Basic Metabolic Research
- National Institutes of Health (P30 DK-45735, R01 AG-023686, R01 DK-056886, R01 DK-093959, R01 DK-40936, R01 DK085577, R01 DK93928, R01 NS-087568, R01-HD 04787, R01-HD028016, R24 DK-085638, R24 DK-090963, T32 DK-101019, U24 DK-059635, UL1 TR-000142)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- hepatic insulin resistance, type 2 diabetes, hepatic glucose production, white adipose tissue inflammation, adipose triglyceride lipase, lipolysis, pyruvate carboxylase, insulin signaling, interleukin-6, obesity, in vivo metabolomics
- MeSH terms
- Acetyl Coenzyme A, Adolescent, Animals, Diabetes Mellitus, Type 2, Glucose, Humans, Hyperglycemia, Insulin Resistance, Lipolysis, Liver, Male, Obesity, Panniculitis, Interleukin-6, Rats, Sprague-Dawley, Mice, Adipose Tissue, White, Diet, High-Fat
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