Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase
Abstract
Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulating food intake, energy expenditure and neuroendocrine function. Leptin stimulates the oxidation of fatty acids and the uptake of glucose, and prevents the accumulation of lipids in nonadipose tissues, which can lead to functional impairments known as "lipotoxicity". The signalling pathways that mediate the metabolic effects of leptin remain undefined. The 5'-AMP-activated protein kinase (AMPK) potently stimulates fatty-acid oxidation in muscle by inhibiting the activity of acetyl coenzyme A carboxylase (ACC). AMPK is a heterotrimeric enzyme that is conserved from yeast to humans and functions as a 'fuel gauge' to monitor the status of cellular energy. Here we show that leptin selectively stimulates phosphorylation and activation of the alpha2 catalytic subunit of AMPK (alpha2 AMPK) in skeletal muscle, thus establishing a previously unknown signalling pathway for leptin. Early activation of AMPK occurs by leptin acting directly on muscle, whereas later activation depends on leptin functioning through the hypothalamic-sympathetic nervous system axis. In parallel with its activation of AMPK, leptin suppresses the activity of ACC, thereby stimulating the oxidation of fatty acids in muscle. Blocking AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. Our data identify AMPK as a principal mediator of the effects of leptin on fatty-acid metabolism in muscle.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
By activating receptors in striated muscle, leptin promotes muscle growth, reduces muscle atrophy, enhances intramuscular glucose uptake, and stimulates fatty acid β-oxidation.
“By activating receptors located in striated muscle, leptin promotes muscle growth, reduces muscle atrophy, and exerts key metabolic effects, such as enhancing intramuscular glucose uptake and stimulating fatty acid β-oxidation”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [98]
The anabolic effects of leptin on muscle are also mediated indirectly through the IGF-1 pathway.
“The anabolic effects of leptin on muscle are also mediated indirectly through the insulin-like growth factor-1 (IGF-1) pathway”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [98]
Leptin has been reported to activate AMPK and mTOR signaling pathways.
“Leptin has also been reported to activate nutrient-sensing enzymes including AMP-activated protein kinase (AMPK) (115) and mammalian target of rapamycin (mTOR) signaling pathways (41)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [115]
Hypothalamic AMPK activity is inhibited by central administration of either insulin or leptin.
“In the hypothalamus, AMPK activity is sensitive not only to changes of nutrient (e.g., glucose) availability, but is inhibited by central administration of either insulin or leptin (115, 208).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [115]
Leptin action in the hypothalamus activates AMPK in skeletal muscle via a mechanism involving the sympathetic branch of the autonomic nervous system.
“recent evidence suggests leptin action in the hypothalamus activates AMPK in skeletal muscle via a mechanism involving the sympathetic branch of the autonomic nervous system (115).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [115]
In rodent models, leptin increased expression of AMP-activated protein kinase and PPARα, activating enzymes of fatty acid oxidation and inhibiting enzymes of lipogenesis.
“In rodent models, leptin increased expression of AMP-activated protein kinase (28) and peroxisome proliferator-activated receptor (PPAR) ␣ (29), activating enzymes of fatty acid oxidation, including carnitine palmitoyl transferase-1 and acyl-CoA oxidase, and inhibiting enzymes of lipogenesis, including acyl-CoA carboxylase and stearoyl-CoA desaturase-1 (28,30).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [28]
Leptin can activate glucose uptake in BAT, as well as glucose uptake and fatty acid oxidation in muscle in an AMPK-dependent manner.
“Leptin can also activate glucose uptake in BAT, as well as glucose uptake and fatty acid oxidation in muscle in an AMPK‐dependent manner 40.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [40]
AMPK is activated by the antidiabetic drugs metformin and rosiglitazone, and by the adipocyte-derived hormones leptin and adiponectin.
“It is also activated by the antidiabetic drugs metformin and rosiglitazone (21-23), and by the adipocyte-derived hormones leptin and adiponectin (24, 25).”
From CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations (2004) · cites this paper as [24]
Cites
Central nervous system control of food intake
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000) · Nature · doi:10.1038/35007534 · Cited by 6,451 · see citing works
Leptin and the regulation of body weight in mammals
Friedman, J. M., & Halaas, J. L. (1998) · Nature · doi:10.1038/27376 · Cited by 5,405 · see citing works
Obesity and insulin resistance
Kahn, B. B., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10842 · Cited by 3,283 · see citing works
Self-citationTHE AMP-ACTIVATED/SNF1 PROTEIN KINASE SUBFAMILY: Metabolic Sensors of the Eukaryotic Cell?
Hardie, D. G., Carling, D., & Carlson, M. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.821 · Cited by 1,436 · see citing works
Self-citationAMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes
Winder, W. W., & Hardie, D. G. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.1.e1 · Cited by 1,000 · see citing works
Receptor-mediated regional sympathetic nerve activation by leptin.
Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L., & Sivitz, W. I. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119532 · Cited by 979 · see citing works
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 · see citing works
Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse.
Jat, P., Noble, M., Ataliotis, P., Tanaka, Y., Yannoutsos, N., Larsen, L., & Kioussis, D. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.12.5096 · Cited by 744 · see citing works
Acute stimulation of glucose metabolism in mice by leptin treatment
Kamohara, S., Burcelin, R., Halaas, J. L., Friedman, J. M., & Charron, M. J. (1997) · Nature · doi:10.1038/38717 · Cited by 708 · see citing works
Malonyl-CoA, fuel sensing, and insulin resistance
Ruderman, N. B., Saha, A. K., Vavvas, D. G., & Witters, L. A. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.276.1.e1 · Cited by 644 · see citing works
The regulation of AMP-activated protein kinase by phosphorylation
STEIN, S. C., Woods, A., Jones, N. A., DAVISON, M. D., & Carling, D. (2000) · Biochemical Journal · doi:10.1042/bj3450437 · Cited by 605 · see citing works
Self-citationLeptin Directly Alters Lipid Partitioning in Skeletal Muscle
Muoio, D. M., Dohm, G. L., Fiedorek, F. T., Tapscott, E. B., Coleman, R., & Dohn, G. L. (1997) · Diabetes · doi:10.2337/diab.46.8.1360 · Cited by 458 · see citing works
Hayashi, T., Hirshman, M. F., Fujii, N., Habinowski, S. A., Witters, L. A., & Goodyear, L. J. (2000) · Diabetes · doi:10.2337/diabetes.49.4.527 · Cited by 447 · see citing works
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 · see citing works
Role of the AMP-activated protein kinase in the cellular stress response
Corton, J. M., Gillespie, J. G., & Hardie, D. G. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00070-1 · Cited by 423 · see citing works
Woods, A., Azzout‐Marniche, D., Foretz, M., STEIN, S. C., Lemarchand, P., Ferré, P., Foufelle, F., & Carling, D. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.18.6704-6711.2000 · Cited by 404 · see citing works
Self-citationContraction-induced Changes in Acetyl-CoA Carboxylase and 5′-AMP-activated Kinase in Skeletal Muscle
Vavvas, D., Apazidis, A., Saha, A. K., Gamble, J., Patel, A., Kemp, B. E., Witters, L. A., & Ruderman, N. B. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.20.13255 · Cited by 395 · see citing works
Ponticos, M., Lu, Q. L., Morgan, J. E., Hardie, D. G., Partridge, T. A., & Carling, D. (1998) · The EMBO Journal · doi:10.1093/emboj/17.6.1688 · Cited by 317 · see citing works
Self-citationH‐2Kb‐tsA58トランスジェニックマウスから直接に無限増殖細胞系を得る方法
Jat, P., Noble, M., Ataliotis, P., Tanaka, Y., Yannoutsos, N., Larsen, L., & Kioussis, D. (1991) · Cited by 310 · see citing works
Minokoshi, Y., Haque, M. S., & Shimazu, T. (1999) · Diabetes · doi:10.2337/diabetes.48.2.287 · Cited by 296 · see citing works
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 · see citing works
Woods, A., Salt, I. P., Scott, J., Hardie, D. G., & Carling, D. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01209-4 · Cited by 261 · see citing works
Self-citationHigaki, Y., Hirshman, M. F., FUJII, N. L., & Goodyear, L. J. (2001) · Diabetes · doi:10.2337/diabetes.50.2.241 · Cited by 254 · see citing works
Fryer, L. G., Hajduch, É., Rencurel, F., Salt, I. P., Hundal, H. S., Hardie, D. G., & Carling, D. (2000) · Diabetes · doi:10.2337/diabetes.49.12.1978 · Cited by 166 · see citing works
Self-citationRegulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation
Goodwin, G. W., & Taegtmeyer, H. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.4.e772 · Cited by 98 · see citing works
AMP-Activated Protein Kinase Is Activated by the Stimulations of Gq-Coupled Receptors
Kishi, K., Yuasa, T., Minami, A., Yamada, M., Hagi, A., Hayashi, H., Kemp, B. E., Witters, L. A., & Ebina, Y. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3417 · Cited by 66 · see citing works
Oakes, N. D., Kjellstedt, A., Forsberg, G., Clementz, T., Camejo, G., Furler, S. M., Kraegen, E. W., Ölwegård-Halvarsson, M., Jenkins, A. B., & Ljung, B. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33520-3 · Cited by 54 · see citing works
Sodium Pump in Skeletal Muscle: Central Nervous System-Induced Suppression by α-Adrenoreceptors
Akaike, N. (1981) · Science · doi:10.1126/science.6267696 · Cited by 41 · see citing works
Autoradiographic delineation of skeletal muscle alpha 1-adrenergic receptor distribution
Martin, W. H., Tolley, T., & Saffitz, J. E. (1990) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1990.259.5.h1402 · Cited by 25 · see citing works
Noradrenergic modulation of the masseteric reflex in behaving cats. I. Pharmacological studies
Stafford, I., & Jacobs, B. (1990) · Journal of Neuroscience · doi:10.1523/jneurosci.10-01-00091.1990 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
den Besten, G., van Eunen, K., Groen, A. K., Venema, K., Reijngoud, D.-J., & Bakker, B. M. (2013) · Journal of Lipid Research · doi:10.1194/jlr.r036012 · Cited by 5,048 · see citing works
Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., et al. (2002) · Nature Medicine · doi:10.1038/nm788 · Cited by 4,238 · see citing works
Self-citationMuscles, exercise and obesity: skeletal muscle as a secretory organ
Pedersen, B. K., & Febbraio, M. A. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.49 · Cited by 2,909 · see citing works
Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799 · see citing works
Self-citationAdiponectin and Adiponectin Receptors
Kadowaki, T., & Yamauchi, T. (2005) · Endocrine Reviews · doi:10.1210/er.2005-0005 · Cited by 2,634 · see citing works
Mechanisms underlying the resistance to diet-induced obesity in germ-free mice
Bäckhed, F., Manchester, J. K., Semenkovich, C. F., & Gordon, J. I. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605374104 · Cited by 2,615 · see citing works
Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6
Pedersen, B. K., & Febbraio, M. A. (2008) · Physiological Reviews · doi:10.1152/physrev.90100.2007 · Cited by 2,388 · see citing works
Adipocytes as regulators of energy balance and glucose homeostasis
Rosen, E. D., & Spiegelman, B. M. (2006) · Nature · doi:10.1038/nature05483 · Cited by 2,170 · see citing works
Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797 · see citing works
Islet cell failure in type 2 diabetes
Prentki, M. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29103 · Cited by 1,690 · see citing works
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function
Hardie, D. G. (2011) · Genes & Development · doi:10.1101/gad.17420111 · Cited by 1,638 · see citing works
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650 · see citing works
Self-citationAMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J., et al. (2004) · Nature · doi:10.1038/nature02440 · Cited by 1,637 · see citing works
Self-citationSaper, C. B., Chou, T. C., & Elmquist, J. K. (2002) · Neuron · doi:10.1016/s0896-6273(02)00969-8 · Cited by 1,120 · see citing works
Stern, J. H., Rutkowski, J. M., & Scherer, P. E. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.011 · Cited by 1,031 · see citing works
Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome
Maury, E., & Brichard, S. M. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.07.031 · Cited by 1,026 · see citing works
Minireview: The AMP-Activated Protein Kinase Cascade: The Key Sensor of Cellular Energy Status
Hardie, D. G. (2003) · Endocrinology · doi:10.1210/en.2003-0982 · Cited by 994 · see citing works
Tomas, E., Tsao, T.-S., Saha, A. K., Murrey, H. E., Zhang, C. C., Itani, S. I., Lodish, H. F., & Ruderman, N. B. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222657499 · Cited by 973 · see citing works
Structure of mammalian AMPK and its regulation by ADP
Xiao, B., Sanders, M. J., Underwood, E., Heath, R., Mayer, F. V., Carmena, D., Jing, C., Walker, P. A., Eccleston, J. F., Haire, L. F., et al. (2011) · Nature · doi:10.1038/nature09932 · Cited by 926 · see citing works
Self-citationAdiponectin Stimulates AMP-Activated Protein Kinase in the Hypothalamus and Increases Food Intake
Kubota, N., Yano, W., Kubota, T., Yamauchi, T., Itoh, S., Kumagai, H., Kozono, H., Takamoto, I., Okamoto, S., Shiuchi, T., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.06.003 · Cited by 844 · see citing works
Self-citationAMP-Activated Protein Kinase – Development of the Energy Sensor Concept
Hardie, D. G., Hawley, S. A., & Scott, J. W. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108944 · Cited by 813 · see citing works
Inflammatory mechanisms in the regulation of insulin resistance
Tilg, H., & Moschen, A. R. (2008) · Molecular Medicine · doi:10.2119/2007-00119.tilg · Cited by 779 · see citing works
Scott, J. W., Hawley, S. A., Green, K. A., Anis, M., Stewart, G., Scullion, G. A., Norman, D. G., & Hardie, D. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19874 · Cited by 754 · see citing works
Adipocytokines in Obesity and Metabolic Disease
Cao, H. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0339 · Cited by 705 · see citing works
Pedersen, B. K. (2011) · Journal of Experimental Biology · doi:10.1242/jeb.048074 · Cited by 668 · see citing works
Leptin in Human Physiology and Pathophysiology
Mantzoros, C. S., Magkos, F., Brinkoetter, M., Sienkiewicz, E., Dardeno, T. A., Kim, S.-Y., Hamnvik, O.-P. R., & Koniaris, A. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00315.2011 · Cited by 593 · see citing works
Structural basis for AMP binding to mammalian AMP-activated protein kinase
Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F., Davis, C. T., et al. (2007) · Nature · doi:10.1038/nature06161 · Cited by 591 · see citing works
Self-citationA liver-derived secretory protein, selenoprotein P, causes insulin resistance
Misu, H., Takamura, T., Takayama, H., Hayashi, H., Matsuzawa-Nagata, N., Kurita, S., Ishikura, K., Ando, H., Takeshita, Y., Ota, T., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.09.015 · Cited by 583 · see citing works
Self-citationRosenbaum, M. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25977 · Cited by 575 · see citing works
Pedersen, B. K. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120033 · Cited by 516 · see citing works
AMPK at the Nexus of Energetics and Aging
Burkewitz, K., Zhang, Y., & Mair, W. B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.002 · Cited by 483 · see citing works
Metformin Inhibits Proinflammatory Responses and Nuclear Factor-κB in Human Vascular Wall Cells
Isoda, K., Young, J. L., Zirlik, A., MacFarlane, L. A., Tsuboi, N., Gerdes, N., Schönbeck, U., & Libby, P. (2006) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000201938.78044.75 · Cited by 499 · see citing works
Obesity and related consequences to ageing
Jura, M., & Kozak, L. P. (2016) · AGE · doi:10.1007/s11357-016-9884-3 · Cited by 473 · see citing works
The role of AMP-activated protein kinase in the action of ethanol in the liver
You, M., Matsumoto, M., Pacold, C. M., Cho, W. K., & Crabb, D. W. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.09.049 · Cited by 469 · see citing works
Coppari, R., Ichinose, M., Lee, C. E., Pullen, A. E., Kenny, C. D., McGovern, R. A., Tang, V., Liu, S. M., Ludwig, T., Chua, S. C., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.004 · Cited by 457 · see citing works
AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome
Ruderman, N., & Prentki, M. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1344 · Cited by 451 · see citing works
Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity
Unger, R. H., & Scherer, P. E. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2010.01.009 · Cited by 436 · see citing works
A high-fat, ketogenic diet induces a unique metabolic state in mice
Kennedy, A. R., Pissios, P., Otu, H., Xue, B., Asakura, K., Furukawa, N., Marino, F. E., Liu, F.-F., Kahn, B. B., Libermann, T. A., et al. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00717.2006 · Cited by 420 · see citing works
Self-citationMiller, E. J., Li, J., Leng, L., McDonald, C., Atsumi, T., Bucala, R., & Young, L. H. (2008) · Nature · doi:10.1038/nature06504 · Cited by 429 · see citing works
AMPK, the metabolic syndrome and cancer
Luo, Z., Saha, A. K., Xiang, X., & Ruderman, N. B. (2005) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2004.12.011 · Cited by 426 · see citing works
AMPK β Subunit Targets Metabolic Stress Sensing to Glycogen
Polekhina, G., Gupta, A., Michell, B. J., van Denderen, B., Murthy, S., Feil, S. C., Jennings, I. G., Campbell, D. J., Witters, L. A., Parker, M. W., et al. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00292-6 · Cited by 423 · see citing works
Rivera, L., Morón, R., Zarzuelo, A., & Galisteo, M. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.11.027 · Cited by 391 · see citing works
AMPK inhibition in health and disease
Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M., Giri, S., & Andreelli, F. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2010.488215 · Cited by 383 · see citing works
Modern science versus the stigma of obesity
Friedman, J. M. (2004) · Nature Medicine · doi:10.1038/nm0604-563 · Cited by 368 · see citing works
The metabolic syndrome: role of skeletal muscle metabolism.
Stump, C. S., Henriksen, E. J., Wei, Y., & Sowers, J. R. (2006) · Annals of Medicine · doi:10.1080/07853890600888413 · Cited by 362 · see citing works
Wojtaszewski, J. F. P., MacDonald, C., Nielsen, J. N., Hellsten, Y., Hardie, D. G., Kemp, B. E., Kiens, B., & Richter, E. A. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00436.2002 · Cited by 348 · see citing works
Sanders, M. J., Ali, Z. S., Hegarty, B. D., Heath, R., Snowden, M. A., & Carling, D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706543200 · Cited by 347 · see citing works
Neurobiology of Feeding and Energy Expenditure
Gao, Q., & Horvath, T. L. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094324 · Cited by 346 · see citing works
Obesity-related derangements in metabolic regulation
Muoio, D. M., & Newgard, C. B. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142512 · Cited by 345 · see citing works
Leptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
“Leptin has also been reported to activate nutrient-sensing enzymes including AMP-activated protein kinase (AMPK) (115) and mammalian target of rapamycin (mTOR) signaling pathways (41), although neither the neuronal subsets nor the molecular mechanism involved have been elucidated.”
BackgroundInfluentialAdipogenesis and aging: does aging make fat go MAD
Kirkland, J. L., Tchkonia, T., Pirtskhalava, T., Han, J., & Karagiannides, I. (2002) · Experimental Gerontology · doi:10.1016/s0531-5565(02)00014-1 · Cited by 339 · see citing works
Xue, B., & Kahn, B. B. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.113217 · Cited by 338 · see citing works
Self-citationLeptin therapy in insulin-deficient type I diabetes
Wang, M.-Y., Chen, L., Clark, G. O., Lee, Y., Stevens, R. D., Ilkayeva, O. R., Wenner, B. R., Bain, J. R., Charron, M. J., Newgard, C. B., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909422107 · Cited by 327 · see citing works
Barnes, B. R., Marklund, S., Steiler, T. L., Walter, M., Hjälm, Amarger, V., Mahlapuu, M., Leng, Y., Johansson, C., Galuska, D., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405533200 · Cited by 317 · see citing works
AMPK: Lessons from transgenic and knockout animals
Viollet, B. (2009) · Frontiers in bioscience · doi:10.2741/3229 · Cited by 314 · see citing works
Obesity‐related leptin regulates Alzheimer's Aβ
Fewlass, D. C., Noboa, K., Pi‐Sunyer, F. X., Johnston, J. M., Yan, S. D., & Tezapsidis, N. (2004) · The FASEB Journal · doi:10.1096/fj.04-2572com · Cited by 308 · see citing works
Leptin and hyperleptinemia - from friend to foe for cardiovascular function
Ren, J. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1810001 · Cited by 305 · see citing works
Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects with Type 2 Diabetes
Sriwijitkamol, A., Coletta, D. K., Wajcberg, E., Balbontin, G. B., Reyna, S. M., Barrientes, J., Eagan, P. A., Jenkinson, C. P., Cersosimo, E., DeFronzo, R. A., et al. (2007) · Diabetes · doi:10.2337/db06-1119 · Cited by 304 · see citing works
Review on leptin and adiponectin responses and adaptations to acute and chronic exercise
Bouassida, A., Chamari, K., Zaouali, M., Feki, Y., Zbidi, A., & Tabka, Z. (2010) · British Journal of Sports Medicine · doi:10.1136/bjsm.2008.046151 · Cited by 290 · see citing works
AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise.
Kelly, M., Keller, C., Avilucea, P. R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A. K., Pedersen, B. K., et al. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.05.188 · Cited by 289 · see citing works
Park, S.-Y., Cho, Y.-R., Kim, H.-J., Higashimori, T., Danton, C., Lee, M.-K., Dey, A., Rothermel, B., Kim, Y.-B., Kalinowski, A., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3530 · Cited by 286 · see citing works
Self-citationAMPK: Regulating Energy Balance at the Cellular and Whole Body Levels
Hardie, D. G., & Ashford, M. L. J. (2014) · Physiology · doi:10.1152/physiol.00050.2013 · Cited by 280 · see citing works
AMP-activated protein kinase regulation and biological actions in the heart
Zaha, V. G., & Young, L. H. (2012) · Circulation Research · doi:10.1161/circresaha.111.255505 · Cited by 279 · see citing works
Cytokines and abnormal glucose and lipid metabolism
Shi, J., Fan, J., Su, Q., & Yang, Z. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00703 · Cited by 282 · see citing works
Inter-organ cross-talk in metabolic syndrome
Priest, C., & Tontonoz, P. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0145-5 · Cited by 279 · see citing works
Xie, Z., Dong, Y., Scholz, R., Neumann, D., & Zou, M.-H. (2008) · Circulation · doi:10.1161/circulationaha.107.744490 · Cited by 273 · see citing works
AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels
Hardie, D. G. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161148 · Cited by 281 · see citing works
Minireview: Malonyl CoA, AMP-Activated Protein Kinase, and Adiposity
Ruderman, N. B., Saha, A. K., & Kraegen, E. W. (2003) · Endocrinology · doi:10.1210/en.2003-0849 · Cited by 266 · see citing works
Acetic Acid Activates Hepatic AMPK and Reduces Hyperglycemia in Diabetic KK-A (y) Mice
Sakakibara, S., Yamauchi, T., Oshima, Y., Tsukamoto, Y., & Kadowaki, T. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.03.176 · Cited by 263 · see citing works
Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise
Jørgensen, S. B., Richter, E. A., & Wojtaszewski, J. F. P. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.109942 · Cited by 261 · see citing works
20 YEARS OF LEPTIN: Human disorders of leptin action
Farooqi, I. S., & O'Rahilly, S. (2014) · Journal of Endocrinology · doi:10.1530/joe-14-0480 · Cited by 280 · see citing works
Engin, A. B. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_8 · Cited by 260 · see citing works
Roepstorff, C., Thiele, M., Hillig, T., Pilegaard, H., Richter, E. A., Wojtaszewski, J. F. P., & Kiens, B. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108720 · Cited by 238 · see citing works
Dimitriadis, G. D., Maratou, E., Kountouri, A., Board, M., & Lambadiari, V. (2021) · Nutrients · doi:10.3390/nu13010159 · Cited by 241 · see citing works
Peroxisome Proliferator Activator Receptor γ Coactivator-1 Expression Is Reduced in Obesity
Crunkhorn, S., Dearie, F., Mantzoros, C., Gami, H., da Silva, W. S., Espinoza, D., Faucette, R., Barry, K., Bianco, A. C., & Patti, M. E. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611214200 · Cited by 236 · see citing works
Rapid transformation of white adipocytes into fat-oxidizing machines
Orci, L., Cook, W. S., Ravazzola, M., Wang, M.-Y., Park, B.-H., Montesano, R., & Unger, R. H. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308258100 · Cited by 234 · see citing works
Role of adiponectin in human skeletal muscle bioenergetics
Civitarese, A. E., Ukropcova, B., Carling, S., Hulver, M., DeFronzo, R. A., Mandarino, L., Ravussin, E., & Smith, S. R. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.002 · Cited by 234 · see citing works
Hypothalamic control of energy balance: insights into the role of synaptic plasticity
Dietrich, M. O., & Horvath, T. L. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.12.005 · Cited by 227 · see citing works
Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy†
Javor, E. D., Ghany, M. G., Cochran, E. K., Oral, E. A., DePaoli, A. M., Premkumar, A., Kleiner, D. E., & Gorden, P. (2005) · Hepatology · doi:10.1002/hep.20672 · Cited by 228 · see citing works
Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy
Javor, E. D., Cochran, E. K., Musso, C., Young, J. R., DePaoli, A. M., & Gorden, P. (2005) · Diabetes · doi:10.2337/diabetes.54.7.1994 · Cited by 226 · see citing works
AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise
Ruderman, N. B., Park, H., Kaushik, V. K., Dean, D., Constant, S., Prentki, M., & Saha, A. K. (2003) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2003.01164.x · Cited by 217 · see citing works
Site and mechanism of leptin action in a rodent form of congenital lipodystrophy
Asilmaz, E., Cohen, P., Miyazaki, M., Dobrzyn, P., Ueki, K., Fayzikhodjaeva, G., Soukas, A. A., Kahn, C. R., Ntambi, J. M., Socci, N. D., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200419511 · Cited by 210 · see citing works
Suwa, M., Egashira, T., Nakano, H., Sasaki, H., & Kumagai, S. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00255.2006 · Cited by 210 · see citing works
Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine
Unger, R. H. (2005) · Biochimie · doi:10.1016/j.biochi.2004.11.014 · Cited by 184 · see citing works
Hwang, J.-H., Stein, D. T., Barzilai, N., Cui, M.-H., Tonelli, J., Kishore, P., & Hawkins, M. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00590.2006 · Cited by 188 · see citing works
Peripheral metabolic actions of leptin
Muoio, D. M., & Lynis Dohm, G. (2002) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1053/beem.2002.0223 · Cited by 183 · see citing works
PPARα is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue
Lee, Y., Yu, X., Gonzales, F., Mangelsdorf, D. J., Wang, M.-Y., Richardson, C., Witters, L. A., & Unger, R. H. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182420899 · Cited by 181 · see citing works
Bruce, C. R., & Dyck, D. J. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00150.2004 · Cited by 178 · see citing works
Inter‐organ communication: a gatekeeper for metabolic health
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C. (2019) · The EMBO Reports · doi:10.15252/embr.201947903 · Cited by 178 · see citing works
The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK
Zhan, Y.-Y., Chen, Y., Zhang, Q., Zhuang, J.-J., Tian, M., Chen, H.-Z., Zhang, L.-R., Zhang, H.-K., He, J.-P., Wang, W.-J., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1069 · Cited by 180 · see citing works
Gong, Y., Ishida-Takahashi, R., Villanueva, E. C., Fingar, D. C., Münzberg, H., & Myers, M. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702838200 · Cited by 173 · see citing works
Xie, Z., Dong, Y., Zhang, M., Cui, M.-Z., Cohen, R. A., Riek, U., Neumann, D., Schlattner, U., & Zou, M.-H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511178200 · Cited by 172 · see citing works
German, J., Kim, F., Schwartz, G. J., Havel, P. J., Rhodes, C. J., Schwartz, M. W., & Morton, G. J. (2009) · Endocrinology · doi:10.1210/en.2009-0445 · Cited by 164 · see citing works
Perdomo, G., Commerford, S. R., Richard, A.-M. T., Adams, S. H., Corkey, B. E., O'Doherty, R. M., & Brown, N. F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403566200 · Cited by 158 · see citing works
Leptin, the obesity‐associated hormone, exhibits direct cardioprotective effects
Smith, C. C. T., Mocanu, M. M., Davidson, S. M., Wynne, A. M., Simpkin, J. C., & Yellon, D. M. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706834 · Cited by 153 · see citing works
Colombo, C., Cutson, J. J., Yamauchi, T., Vinson, C., Kadowaki, T., Gavrilova, O., & Reitman, M. L. (2002) · Diabetes · doi:10.2337/diabetes.51.9.2727 · Cited by 147 · see citing works
Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism
Hardie, D. G. (2011) · Proceedings of the Nutrition Society · doi:10.1017/s0029665110003915 · Cited by 146 · see citing works
Musso, C., Cochran, E., Javor, E., Young, J., DePaoli, A. M., & Gorden, P. (2005) · Metabolism · doi:10.1016/j.metabol.2004.08.021 · Cited by 146 · see citing works
De Bock, K., Richter, E. A., Russell, A. P., Eijnde, B. O., Derave, W., Ramaekers, M., Koninckx, E., Léger, B., Verhaeghe, J., & Hespel, P. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.083170 · Cited by 145 · see citing works
AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction
Turdi, S., Fan, X., Li, J., Zhao, J., Huff, A. F., Du, M., & Ren, J. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00586.x · Cited by 141 · see citing works
- Authors
- Minokoshi, Y., Kim, Y.-B., Peroni, O. D., Fryer, L. G. D., Müller, C., Carling, D., & Kahn, B. B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Hammersmith Hospital (GB)
- Corresponding author
- Kahn, Barbara B.
- Venue
- Nature
- Published
- 2002-01-17
- Volume
- 415
- Issue
- 6869
- Pages
- 339-343
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2042444876
- Cited by
- 2,053
- References
- 30
- Citations by year
- 2026: 19 · 2025: 39 · 2024: 37 · 2023: 48 · 2022: 51 · 2021: 65 · 2020: 64 · 2019: 54 · 2018: 59 · 2017: 80 · 2016: 75 · 2015: 73 · 2014: 88 · 2013: 107 · 2012: 106
- FWCI
- 43.29
- Type
- journal article
- Language
- en
- Update notices
- expression_of_concern (2024-05-06)
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- leptin, AMPK, fatty acid oxidation, skeletal muscle, acetyl-CoA carboxylase, lipotoxicity, energy homeostasis
- MeSH terms
- Acetyl-CoA Carboxylase, Adrenergic alpha-Antagonists, Adrenergic beta-Agonists, Animals, Enzyme Activation, Fatty Acids, Isoproterenol, Male, Multienzyme Complexes, Oxidation-Reduction, Phentolamine, Phosphorylation, Sympathetic Nervous System, Signal Transduction, Protein Serine-Threonine Kinases, Muscle, Skeletal, Catalytic Domain, Leptin, Lipid Metabolism, Mice, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
