The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.
Lipotoxic Diseases
Abstract
I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic beta-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipid-laden cells, such as beta-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents.
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“Steatosis occurs with decreased leptin action, whether due to leptin deficiency or resistance.9”
From Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy† (2005) · cites this paper as [9]
Citations
Cites
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419
Weight-Reducing Effects of the Plasma Protein Encoded by the obese Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451
Effects of the obese Gene Product on Body Weight Regulation in ob / ob Mice
Pelleymounter, M. A., Cullen, M. J., Baker, M. B., Hecht, R., Winters, D., Boone, T., & Collins, F. (1995) · Science · doi:10.1126/science.7624776 · Cited by 4,017
Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R., & Burn, P. (1995) · Science · doi:10.1126/science.7624778 · Cited by 3,243
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., et al. (1997) · Nature · doi:10.1038/43185 · Cited by 2,936
Obesity and the regulation of energy balance
Spiegelman, B. M., & Flier, J. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00240-9 · Cited by 2,398
A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction
Clément, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J.-M., et al. (1998) · Nature · doi:10.1038/32911 · Cited by 2,346
Abnormal splicing of the leptin receptor in diabetic mice
Lee, G.-H., Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., & Friedman, J. M. (1996) · Nature · doi:10.1038/379632a0 · Cited by 2,327
Programmed Cell Death Induced by Ceramide
Obeid, L. M., Linardic, C. M., Karolak, L. A., & Hannun, Y. A. (1993) · Science · doi:10.1126/science.8456305 · Cited by 1,794
Adipose Tissue as an Endocrine Organ
Ahima, R. S., & Flier, J. S. (2000) · Trends in Endocrinology & Metabolism · doi:10.1016/s1043-2760(00)00301-5 · Cited by 1,608
The role of neuropeptide Y in the antiobesity action of the obese gene product
Stephens, T. W., Basinski, M., Bristow, P. K., Bue-Valleskey, J. M., Burgett, S. G., Craft, L., Hale, J., Hoffmann, J., Hsiung, H. M., Kriauciunas, A., et al. (1995) · Nature · doi:10.1038/377530a0 · Cited by 1,498
Kliewer, S. A., FORMAN, B. M., Blumberg, B., Ong, E. S., Borgmeyer, U., Mangelsdorf, D. J., Umesono, K., & Evans, R. M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.15.7355 · Cited by 1,402
Lipotoxic heart disease in obese rats: Implications for human obesity
Zhou, Y.-T., Grayburn, P., Karim, A., Shimabukuro, M., Higa, M., Baetens, D., Orci, L., & Unger, R. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1784 · Cited by 1,265
Self-citationPathophysiology of insulin resistance in human disease
Reaven, G. M. (1995) · Physiological Reviews · doi:10.1152/physrev.1995.75.3.473 · Cited by 1,226
Fatty acid-induced β cell apoptosis: A link between obesity and diabetes
Shimabukuro, M., Zhou, Y.-T., Levi, M., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2498 · Cited by 1,142
Self-citationLeptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.
Vaisse, C., Halaas, J. L., Horvath, C. M., Darnell, J. E., Stoffel, M., & Friedman, J. M. (1996) · Nature Genetics · doi:10.1038/ng0996-95 · Cited by 1,086
Schoonjans, K., Staels, B., & Auwerx, J. H. (1996) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(96)00066-5 · Cited by 1,045
Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy
Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S., & Goldstein, J. L. (1999) · Nature · doi:10.1038/43448 · Cited by 1,038
Reduced Food Intake and Body Weight in Mice Treated with Fatty Acid Synthase Inhibitors
Loftus, T. M., Jaworsky, D. E., Frehywot, G. L., Townsend, C. A., Ronnett, G. V., Lane, M. D., & Kuhajda, F. P. (2000) · Science · doi:10.1126/science.288.5475.2379 · Cited by 1,004
Leptin: The Tale of an Obesity Gene
Caro, J. F., Sinha, M. K., Kolaczynski, J. W., Zhang, P. L., & Considine, R. V. (1996) · Diabetes · doi:10.2337/diab.45.11.1455 · Cited by 982
Keller, H., Dreyer, C., Medin, J. A., Mahfoudi, A., Ozato, K., & Wahli, W. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.6.2160 · Cited by 944
Role of Insulin Resistance in Human Disease (Syndrome X): An Expanded Definition
Reaven, G. M. (1993) · Annual Review of Medicine · doi:10.1146/annurev.me.44.020193.001005 · Cited by 908
Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2
Abu-Elheiga, L., Matzuk, M. M., Abo-Hashema, K. A. H., & Wakil, S. J. (2001) · Science · doi:10.1126/science.1056843 · Cited by 903
Lee, Y., Hirose, H., Ohneda, M., Johnson, J. H., McGarry, J., & Unger, R. H. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.10878 · Cited by 832
Self-citationLeptin receptor missense mutation in the fatty Zucker rat
Phillips, M. S., Liu, Q., Hammond, H. A., Dugan, V., Hey, P. J., Caskey, C. T., & Hess, J. F. (1996) · Nature Genetics · doi:10.1038/ng0596-18 · Cited by 822
The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP
Ricquier, D., & Bouillaud, F. (2000) · Biochemical Journal · doi:10.1042/bj3450161 · Cited by 811
Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome
Alpert, M. A. (2001) · The American Journal of the Medical Sciences · doi:10.1097/00000441-200104000-00003 · Cited by 795
A novel mouse model of lipotoxic cardiomyopathy
Chiu, H.-C., Kovács, A., Ford, D. A., Hsu, F., Garcia, R. A., Herrero, P., Saffitz, J. E., & Schaffer, J. E. (2001) · Journal of Clinical Investigation · doi:10.1172/jci10947 · Cited by 762
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121164498 · Cited by 753
A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis.
McGarry, J. D., Mannaerts, G. P., & Foster, D. W. (1977) · Journal of Clinical Investigation · doi:10.1172/jci108764 · Cited by 736
What if Minkowski Had Been Ageusic? An Alternative Angle on Diabetes
McGarry, J. D. (1992) · Science · doi:10.1126/science.1439783 · Cited by 657
Direct antidiabetic effect of leptin through triglyceride depletion of tissues
Shimabukuro, M., Koyama, K., Chen, G., Wang, M.-Y., Trieu, F., Lee, Y., Newgard, C. B., & Unger, R. H. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4637 · Cited by 646
Self-citationLipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover.
Unger, R. H., & Zhou, Y. (2001) · Diabetes · doi:10.2337/diabetes.50.2007.s118 · Cited by 476
Self-citationA family of fatty acid transporters conserved from mycobacterium to man
Hirsch, D., Stahl, A., & Lodish, H. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.15.8625 · Cited by 454
Regulation of fatty acid homeostasis in cells: Novel role of leptin
Unger, R. H., Zhou, Y.-T., & Orci, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.5.2327 · Cited by 435
Self-citationDiseases of liporegulation: new perspective on obesity and related disorders
Unger, R. H., & Orci, L. (2001) · The FASEB Journal · doi:10.1096/fj.00-0590 · Cited by 429
Self-citationLipoapoptosis in Beta-cells of Obese Prediabeticfa/fa Rats
Shimabukuro, M., Higa, M., Zhou, Y.-T., Wang, M.-Y., Newgard, C. B., & Unger, R. H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.32487 · Cited by 394
Self-citationGlucagon physiology and pathophysiology in the light of new advances
Unger, R. H. (1985) · Diabetologia · doi:10.1007/bf00281991 · Cited by 361
Self-citationMembrane transport of long-chain fatty acids: evidence for a facilitated process
Abumrad, N. A., Harmon, C. M., & Ibrahimi, A. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33310-1 · Cited by 326
The “Thrifty Genotype” in 19981
Neel, J. V. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.1999.tb01782.x · Cited by 324
Fatty acid transport: difficult or easy?
Hamilton, J. A. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33287-9 · Cited by 323
Generalized lipodystrophy, congenital and acquired (lipoatrophy)
Seip, M., & Trygstad, O. (1996) · Acta Paediatrica · doi:10.1111/j.1651-2227.1996.tb14262.x · Cited by 293
Bergeron, R., Previs, S. F., Cline, G. W., Perret, P., Russell, R. R., Young, L. H., & Shulman, G. I. (2001) · Diabetes · doi:10.2337/diabetes.50.5.1076 · Cited by 285
Role of nitric oxide in obesity-induced beta cell disease.
Shimabukuro, M., Ohneda, M., Lee, Y., & Unger, R. H. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119534 · Cited by 282
Self-citationLiporegulation in Diet-induced Obesity
Lee, Y., Wang, M.-Y., Kakuma, T., Wang, Z.-W., Babcock, E. E., McCorkle, K., Higa, M., Zhou, Y.-T., & Unger, R. H. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008553200 · Cited by 269
Self-citationMilburn, J. L., Hirose, H., Lee, Y. H., Nagasawa, Y., Ogawa, A., Ohneda, M., BeltrandelRio, H., Newgard, C. B., Johnson, J. H., & Unger, R. H. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.3.1295 · Cited by 269
Self-citationKakuma, T., Lee, Y., Higa, M., Wang, Z.-W., Pan, W., Shimomura, I., & Unger, R. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.15.8536 · Cited by 261
Self-citationInhibition of fatty acid and cholesterol synthesis by stimulation of AMP‐activated protein kinase
Henin, N., Vincent, M. F., Gruber, H. E., & Berghe, G. (1995) · The FASEB Journal · doi:10.1096/fasebj.9.7.7737463 · Cited by 251
Troglitazone Lowers Islet Fat and Restores Beta Cell Function of Zucker Diabetic Fatty Rats
Shimabukuro, M., Zhou, Y.-T., Lee, Y., & Unger, R. H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.6.3547 · Cited by 249
Self-citationAlpert, M. A., & Hashimi, M. W. (1993) · The American Journal of the Medical Sciences · doi:10.1097/00000441-199308000-00011 · Cited by 245
Higa, M., Zhou, Y.-T., Ravazzola, M., Baetens, D., Orci, L., & Unger, R. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.20.11513 · Cited by 233
Self-citationProtection against lipoapoptosis of β cells through leptin-dependent maintenance of Bcl-2 expression
Shimabukuro, M., Wang, M.-Y., Zhou, Y.-T., Newgard, C. B., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9558 · Cited by 213
Self-citationHuman and Murine Serine‐Palmitoyl‐CoA Transferase
Weiss, B., & Stoffel, W. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.00239.x · Cited by 205
Iida, M., Murakami, T., Ishida, K., Mizuno, A., Kuwajima, M., & Shima, K. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.1070 · Cited by 185
Lipodystrophy in patients naive to HIV protease inhibitors
Madge, S., Loes, S. K., Mercey, D., Johnson, M. A., & Weller, I. V. D. (1999) · AIDS · doi:10.1097/00002030-199904160-00020 · Cited by 184
Increased Lipogenic Capacity of the Islets of Obese Rats: A Role in the Pathogenesis of NIDDM
Lee, Y., Hiros, H., Zhou, Y.-T., Esser, V., McGarry, J., & Unger, R. H. (1997) · Diabetes · doi:10.2337/diab.46.3.408 · Cited by 184
Self-citationLeptin plasma concentrations are dependent on body fat distribution in obese patients
Minocci, A., Savia, G., Lucantoni, R., Berselli, M. E., Tagliaferri, M., Calò, G., Petroni, M. L., Medici, C. D., Viberti, G., & Liuzzi, A. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801385 · Cited by 176
Role of peroxisome proliferator-activated receptor α in disease of pancreatic β cells
Zhou, Y.-T., Shimabukuro, M., Wang, M.-Y., Lee, Y., Higa, M., Milburn, J. L., Newgard, C. B., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.15.8898 · Cited by 173
Self-citationAlexander, J. K. (1985) · Progress in Cardiovascular Diseases · doi:10.1016/s0033-0620(85)80002-5 · Cited by 169
The role of leptin resistance in the lipid abnormalities of aging
WANG, Z.-W., Pan, W., Lee, Y., Kakuma, T., ZHOU, Y.-T., & Unger, R. H. (2001) · The FASEB Journal · doi:10.1096/fj.00-0310com · Cited by 146
Self-citationKakuda, T. N., Brundage, R. C., Anderson, P. L., & Fletcher, C. V. (1999) · AIDS · doi:10.1097/00002030-199911120-00019 · Cited by 144
Ohneda, M., Inman, L. R., & Unger, R. H. (1995) · Diabetologia · doi:10.1007/bf00400091 · Cited by 110
Self-citationDisruption of the Relationship between Fat Content and Leptin Levels with Aging in Humans
Møller, N., O’Brien, P. C., & Nair, K. S. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.3.4620 · Cited by 107
OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype
Wang, M.-Y., Koyama, K., Shimabukuro, M., Newgard, C. B., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.2.714 · Cited by 102
Self-citationWang, M.-Y., Koyama, K., Shimabukuro, M., Mangelsdorf, D. J., Newgard, C. B., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.20.11921 · Cited by 98
Self-citationAdipose tissue as an endocrine organ
Ailhaud, G. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801267 · Cited by 79
Zhou, Y., Shimabukuro, M., Lee, Y., Koyama, K., Higa, M., Ferguson, T., & Unger, R. H. (1998) · Diabetes · doi:10.2337/diabetes.47.12.1904 · Cited by 75
Self-citationLeptin physiology: a second look
Unger, R. H. (2000) · Regulatory Peptides · doi:10.1016/s0167-0115(00)00154-3 · Cited by 68
Self-citationCardiac findings in generalized lipodystrophy*
Bjørnstad, P., FOERSTER, A., & Ihlen, H. (1996) · Acta Paediatrica · doi:10.1111/j.1651-2227.1996.tb14264.x · Cited by 49
Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM
Lee, Y., Hirose, H., Zhou, Y. T., et al. (1997) · Diabetes · doi:10.2337/diabetes.46.3.408 · Cited by 47
Surwit, R. S., Edwards, C. L., Murthy, S., & Petro, A. E. (2000) · Diabetes · doi:10.2337/diabetes.49.7.1203 · Cited by 39
Hennessey, T. M., Andrews, D. A., & Nelson, D. L. (1983) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37962-1 · Cited by 30
Ohneda, M., Inman, L. R., & Unger, R. H. (1995) · Diabetologia · doi:10.1007/s001250050267 · Cited by 9
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Metadata
- Authors
- Unger, R. H.
- Affiliations
- Dallas VA Medical Center (US)
- Corresponding author
- Unger, Roger H.
- Venue
- Annual Review of Medicine
- Publisher
- Annual Reviews
- Published
- 2002-02
- Volume
- 53
- Issue
- 1
- Pages
- 319-336
- ISSN
- 0066-4219 (ISSN-L)
- 1545-326X
- OpenAlex
- W4254261652
- Cited by
- 875
- References
- 71
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 25 · 2023: 15 · 2022: 18 · 2021: 31 · 2020: 22 · 2019: 21 · 2018: 22 · 2017: 30 · 2016: 32 · 2015: 30 · 2014: 29 · 2013: 49 · 2012: 34
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- leptin, lipotoxicity, lipid homeostasis, lipoapoptosis, leptin resistance, leptin deficiency, lipodystrophy, leptin receptor mutation, diet-induced obesity, type 2 diabetes, cardiomyopathy, insulin resistance, metabolic syndrome, ceramide, nitric oxide, caloric restriction, thiazolidinediones, obesity complications
- MeSH terms
- Adipose Tissue, Animals, Homeostasis, Humans, Lipids, Myocardium, Obesity, Risk Factors, Leptin, Metabolic Syndrome
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