Leptin selectively decreases visceral adiposity and enhances insulin action
Open accessAbstract
Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance.
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High leptin levels may lead to insulin resistance in nonobese PCOS patients by promoting four events: inhibition of phosphoenolpyruvate carboxykinase, fat deposition in skeletal muscle cells, fat breakdown and free fatty acid production, and direct inhibition of basal and glucose-stimulated insulin secretion.
“High leptin levels may lead to IR in nonobese PCOS patients by promoting the following events: (i) inhibition of phosphoenolpyruvate carboxykinase, causing decreased hepatic glucose oxidation and increased hepatic glycogen reserve; (ii) fat deposition in skeletal muscle cells; (iii) fat breakdown and free fatty acid production; and (iv) direct inhibition of basal insulin secretion and glucose-stim”
From Circulating Adipokine Levels in Nonobese Women with Polycystic Ovary Syndrome and in Nonobese Control Women: A Systematic Review and Meta-Analysis (2021) · cites this paper as [34]
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“uniformly (96), and that leptin can decrease adiposity independent of food intake (198, 199), the electrophys-”
Ingvartsen, K. L., & Boisclair, Y. R. (2001) · Domestic Animal Endocrinology · doi:10.1016/s0739-7240(02)00119-4 · Cited by 195 · see citing works
Wolf, G., & Ziyadeh, F. N. (2006) · KARGER eBooks · doi:10.1159/000095328 · Cited by 193 · see citing works
Hypothalamic Responses to Long-chain Fatty Acids Are Nutritionally Regulated
Morgan, K., Obici, S., & Rossetti, L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400458200 · Cited by 187 · see citing works
You, T., Yang, R., Lyles, M. F., Gong, D., & Nicklas, B. J. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00419.2004 · Cited by 173 · see citing works
“Animal studies have shown that leptin (3) or adiponectin (26) administration significantly reduces visceral adiposity in rodents.”
BackgroundBates, S. H., Kulkarni, R. N., Seifert, M., & Myers, M. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.02.001 · Cited by 173 · see citing works
“174 and feeding (Petersen et al., 2002; Oral et al., 2002; Shimomura et al., 1999; Colombo et al., 2002; Ebihara et al., 2001; Liu et al., 1998; Burcelin et al., 1999; Kamohara et al., 1997; Barzilai et al., 1999).”
BackgroundGavi, S., Stuart, L. M., Kelly, P., Meléndez, M. M., Mynarcik, D. C., Gelato, M. C., & McNurlan, M. A. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1815 · Cited by 167 · see citing works
High-fat diet-induced muscle insulin resistance: relationship to visceral fat mass
Kim, J., Nolte, L. A., Hansen, P. A., Han, D., Ferguson, K., Thompson, P. A., & Holloszy, J. O. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.6.r2057 · Cited by 161 · see citing works
“Does fish oil, which has been reported to protect against the insulin resistance induced in rats by a high-fat diet (36), also protect against visceral fat accumulation? Does leptin administration, which has been reported to selectively decrease visceral fat (2), reverse the muscle insulin resistance that results from…”
BackgroundSexual Dimorphism in Body Fat Distribution and Risk for Cardiovascular Diseases
Nedungadi, T. P., & Clegg, D. J. (2009) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-009-9101-1 · Cited by 154 · see citing works
“Female rats are more responsive than males to the effects of centrally administered leptin to decrease food intake and body weight, and this has been demonstrated to be due to increased leptininduced Stat3 activation in the basal hypothalamus [ 5 , 29].”
BackgroundLeptin Resistance During Aging Is Independent of Fat Mass
Gabriely, I., Xiao, H., Yang, X. M., Rossetti, L., & Barzilai, N. (2002) · Diabetes · doi:10.2337/diabetes.51.4.1016 · Cited by 153 · see citing works
“The rate of glycolysis was estimated from the rate of conversion of [(3)H-3]glucose to (3)H2O as previously described (12,13).”
BackgroundMethodRevisiting the Role of Fat Mass in the Life Extension Induced by Caloric Restriction
Barzilai, N., & Gupta, G. (1999) · The Journals of Gerontology Series A · doi:10.1093/gerona/54.3.b89 · Cited by 152 · see citing works
Moraes, R., Blondet, A., Birkenkamp-Demtroeder, K., Tirard, J., Orntoft, T. F., Gertler, A., Durand, P., Naville, D., & Bégeot, M. (2003) · Endocrinology · doi:10.1210/en.2003-0456 · Cited by 149 · see citing works
Fat Accumulation, Leptin, and Hypercapnia in Obstructive Sleep Apnea-Hypopnea Syndrome
Shimura, R., Tatsumi, K., Nakamura, A., Kasahara, Y., Tanabe, N., Takiguchi, Y., & Kuriyama, T. (2005) · CHEST Journal · doi:10.1378/chest.127.2.543 · Cited by 149 · see citing works
The role of leptin in glucose homeostasis
Denroche, H. C., Huynh, F. K., & Kieffer, T. J. (2012) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2012.00203.x · Cited by 147 · see citing works
Tumor necrosis factor α and insulin resistance in obese type 2 diabetic patients
Miyazaki, Y., Pipek, R., Mandarino, L. J., & DeFronzo, R. A. (2003) · International Journal of Obesity · doi:10.1038/sj.ijo.0802187 · Cited by 148 · see citing works
Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats
Levin, B. E., Dunn-Meynell, A. A., Ricci, M. R., & Cummings, D. E. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00186.2003 · Cited by 141 · see citing works
“Chronic leptin administration promotes weight loss, and ablation of leptin signaling leads to massive obesity (6, 19, 22).”
BackgroundRelation between leptin and the regulation of glucose metabolism
Frühbeck, G., & Salvador, J. (2000) · Diabetologia · doi:10.1007/s001250050002 · Cited by 137 · see citing works
Meli, R., Mattace Raso, G., & Calignano, A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00177 · Cited by 137 · see citing works
“Some studies have provided information on the liver disease progression among patients with NASH, for example, those conducted in patients with lipodystrophy, a pathology characterized by reduction of peripheral fat deposition, severe hepatic steatosis, and diabetes, all conditions reversed by leptin administration (1…”
BackgroundSleep Oxygen Desaturation and Circulating Leptin in Obstructive Sleep Apnea-Hypopnea Syndrome
Tatsumi, K., Kasahara, Y., Kurosu, K., Tanabe, N., Takiguchi, Y., & Kuriyama, T. (2005) · CHEST Journal · doi:10.1378/chest.127.3.716 · Cited by 133 · see citing works
AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment
Steinberg, G. R., Rush, J. W. E., & Dyck, D. J. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00318.2002 · Cited by 133 · see citing works
“5 mg kg 1 day 1 was used as in previous studies (2, 11, 30).”
Obesity and cardiovascular disease
Sowers, J. R. (1998) · Clinical Chemistry · doi:10.1093/clinchem/44.8.1821 · Cited by 125 · see citing works
“It has recently been observed that leptin administration to rodents selectively decreases visceral adiposity and enhances insulin action (77).”
BackgroundPhysiological Increase in Plasma Leptin Markedly Inhibits Insulin Secretion In Vivo
Cases, J. A., Gabriely, I., Xiao, H., Yang, X. M., Michaeli, T., Fleischer, N., Rossetti, L., & Barzilai, N. (2001) · Diabetes · doi:10.2337/diabetes.50.2.348 · Cited by 128 · see citing works
“Leptin action has also been reported in peripheral tissues such as fat, muscle, and liver (3,4).”
BackgroundMulligan, K., Khatami, H., Schwarz, J.-M., Sakkas, G. K., DePaoli, A. M., Tai, V. W., Wen, M. J., Lee, G. A., Grunfeld, C., & Schambelan, M. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1588 · Cited by 127 · see citing works
Diabetes, lipids, and adipocyte secretagogues
Faraj, M., Lu, H. L., & Cianflone, K. (2004) · Biochemistry and Cell Biology · doi:10.1139/o03-078 · Cited by 127 · see citing works
“5 mM (Barzilai et al. 1997).”
Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats
Lin, C.-Y., Higginbotham, D. A., Judd, R. L., & White, B. D. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00489.2001 · Cited by 124 · see citing works
“These data are consistent with studies that have found leptin, administered either centrally or peripherally, to increase insulin-stimulated glucose utilization in peripheral tissues in normal (nondiabetic) rats (2, 7, 33, 37, 42).”
ResultLeptin Impairs Insulin Signaling in Rat Adipocytes
Pérez, C., Fernández‐Galaz, C., Fernández‐Agulló, T., Arribas, C., Andrés, A., Ros, M., & Carrascosa, J. M. (2004) · Diabetes · doi:10.2337/diabetes.53.2.347 · Cited by 124 · see citing works
Murray, I. V. J., Havel, P. J., Sniderman, A. D., & Cianflone, K. (2000) · Endocrinology · doi:10.1210/endo.141.3.7364 · Cited by 122 · see citing works
High Dietary Sodium Intake Increases White Adipose Tissue Mass and Plasma Leptin in Rats
Fonseca‐Alaniz, M. H., Brito, L. C., Borges‐Silva, C. N., Takada, J., Andreotti, S., & Lima, F. B. (2007) · Obesity · doi:10.1038/oby.2007.261 · Cited by 121 · see citing works
“In accordance with this recently conceived concept regarding leptin physiology (40), animals on an HS diet are resistant to metabolic (satiety, body weight, and adipose mass-reducing) effects of leptin in rodents (41,42), but leptin’s sympatho-excitatory actions still remain intact.”
BackgroundCaloric restriction, body fat and ageing in experimental models
Das, M., Gabriely, I., & Barzilai, N. (2004) · Obesity Reviews · doi:10.1111/j.1467-789x.2004.00115.x · Cited by 121 · see citing works
“In this experiment, the action of insulin to suppress EGP was significantly affected by removal 16 Caloric restriction, body fat and ageing M. Das et al. obesity reviews of VF. VF– group demonstrated significant increase in the ability of insulin to suppress the glucose production compared to old SC– group.”
BackgroundInfluentialLeptin and incident type 2 diabetes: risk or protection?
Schmidt, M. I., Duncan, B. B., Vigo, Á., Pankow, J. S., Couper, D. J., Ballantyne, C. M., Hoogeveen, R. C., HEISS, G. M., & For the ARIC Investigators (2006) · Diabetologia · doi:10.1007/s00125-006-0351-z · Cited by 118 · see citing works
“Resistance to leptin’s hepatic actions leads not only to hepatic steatosis [37], but also to increased hepatic gluconeogenesis [28].”
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Harrison, S. A., & Neuschwander‐Tetri, B. A. (2004) · Clinics in Liver Disease · doi:10.1016/j.cld.2004.06.008 · Cited by 115 · see citing works
“Leptin infusion in leptin-deficient ob/ob mice significantly decreases hepatic tryglyceride content [61], and when given to rats, visceral fat content is decreased and the action of insulin on both peripheral glucose uptake and glycogen synthesis is enhanced [62].”
BackgroundThe effect of PPARγ ligands on the adipose tissue in insulin resistance
Hammarstedt, A., Andersson, C. X., Sopasakis, V. R., & Smith, U. (2005) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2005.04.008 · Cited by 117 · see citing works
“Leptin expression and secretion are induced upon insulin signaling, but increased plasma levels of leptin reduce insulin release and improve insulin signaling [90–92].”
BackgroundMelanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes
Gutiérrez-Juárez, R., Obici, S., & Rossetti, L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408665200 · Cited by 115 · see citing works
Improved beta-cell function after standardized weight reduction in severely obese subjects.
Guldstrand, M., Bo, A.-R., & Adamson, U. (2003) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00325.2002 · Cited by 126 · see citing works
“Leptin has previously been shown to improve insulin resistance in rats (6), and recently an inrease in insulin sensitivity has been reported after leptin administration to humans with lipodystrophy (32, 33).”
BackgroundBuettner, R., Newgard, C. B., Rhodes, C. J., & O'Doherty, R. M. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.3.e563 · Cited by 112 · see citing works
“The ability of leptin administration to reverse metabolic abnormalities in the ob/ob mouse (17, 21, 24) and improve insulin action in normal animals (1, 5, 26) has led to the proposal that leptin may serve as an effective therapy for human obesity.”
BackgroundCNS Regulation of Glucose Homeostasis
Lam, C., Chari, M., & Lam, T. K. T. (2009) · Physiology · doi:10.1152/physiol.00003.2009 · Cited by 110 · see citing works
“Chronic increases in plasma leptin, independent of changes in weight, enhances both hepatic and extrahepatic insulin action under pancreatic clamp settings as well as reverses insulin resistance and improves glucose homeostasis in lipodystropic rodents (7, 33, 111).”
BackgroundHidaka, S., Yoshimatsu, H., Kondou, S., Tsuruta, Y., Oka, K., Noguchi, H., Okamoto, K., Sakino, H., Teshima, Y., Okeda, T., et al. (2002) · The FASEB Journal · doi:10.1096/fj.01-0164com · Cited by 108 · see citing works
“Regulation of gene expression in the liver, as shown in the present study, is both consistent (29) and inconsistent (9, 10, 17) with previous studies.”
Marked hyperleptinemia after high-fat diet associated with severe glucose intolerance in mice
Åhrén, B., & Scheurink, A. J. W. (1998) · European Journal of Endocrinology · doi:10.1530/eje.0.1390461 · Cited by 108 · see citing works
“However, the potential role of leptin in this regard is not yet resolved, since leptin also has been demonstrated to augment insulin action (34, 36 ).”
BackgroundLeptin: obesity, diabetes and other peripheral effects - a review
Moran, O., & Phillip, M. (2003) · Pediatric Diabetes · doi:10.1034/j.1399-5448.2003.00017.x · Cited by 107 · see citing works
Yamashita, H., Shao, J., Ishizuka, T., Klepcyk, P. J., Muhlenkamp, P., Qiao, L., Hoggard, N., & Friedman, J. E. (2001) · Endocrinology · doi:10.1210/endo.142.7.8227 · Cited by 113 · see citing works
Kapsimalis, F., Varouchakis, G., Manousaki, A., Daskas, S., Nikita, D., Kryger, M. H., & Gourgoulianis, K. I. (2008) · Lung · doi:10.1007/s00408-008-9082-x · Cited by 106 · see citing works
IL-6-Like Cytokines and Cancer Cachexia: Consequences of Chronic Inflammation
Barton, B. E. (2001) · Immunologic Research · doi:10.1385/ir:23:1:41 · Cited by 106 · see citing works
Jouffe, C., Weger, B. D., Martín, E., Atger, F., Weger, M., Gobet, C., Ramnath, D., Charpagne, A., Morin‐Rivron, D., Powell, E. E., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2200083119 · Cited by 107 · see citing works
Differential Effects of Leptin in Regulation of Tissue Glucose Utilization in Vivo
Wang, J., Chinookoswong, N., Scully, S. A., Qi, M., & Shi, Z. (1999) · Endocrinology · doi:10.1210/endo.140.5.6681 · Cited by 105 · see citing works
Gallardo, N., Bonzón‐Kulichenko, E., Fernández‐Agulló, T., Moltó, E., Gómez‐Alonso, S., Blanco, P., Carrascosa, J. M., Ros, M., & Andrés, A. (2007) · Endocrinology · doi:10.1210/en.2007-0933 · Cited by 105 · see citing works
“Euglycemic-hyperinsulinemicclamp experiments have demonstrated that peripheral (26) or intrahypothalamic leptin infusion (27) increases the whole-body insulin sensitivityintermsofglucosemetabolism.”
BackgroundSteinberg, G. R., Bonen, A., & Dyck, D. J. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00303.2001 · Cited by 102 · see citing works
“This may be due to one of two possible mechanisms: 1) selective depletion of the labile visceral adipose stores (3) or 2) retention of the FA within the adipocyte for oxidation as a result of increased activity of CPT-I, acyl-CoA oxidase, and uncoupling protein (UCP)-1 expression in this tissue (12, 29, 30).”
BackgroundMethodXia, Z., Sniderman, A. D., & Cianflone, K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207281200 · Cited by 97 · see citing works
Irani, B. G., Dunn-Meynell, A. A., & Levin, B. E. (2006) · Endocrinology · doi:10.1210/en.2006-1126 · Cited by 99 · see citing works
Hirose, Y. (2003) · Carcinogenesis · doi:10.1093/carcin/bgh059 · Cited by 96 · see citing works
Maternal leptin is elevated during pregnancy in sheep
Ehrhardt, R., Slepetis, R. M., Bell, A. W., & Boisclair, Y. R. (2001) · Domestic Animal Endocrinology · doi:10.1016/s0739-7240(01)00108-4 · Cited by 96 · see citing works
Size at birth and plasma leptin concentrations in adult life
Phillips, D., Fall, C., Cooper, C. C., Norman, R. J., Robinson, J., & Owens, P. C. (1999) · International Journal of Obesity · doi:10.1038/sj.ijo.0801050 · Cited by 93 · see citing works
Wolden‐Hanson, T. (2000) · Endocrinology · doi:10.1210/en.141.2.487 · Cited by 92 · see citing works
“A final potential explanation for the selective decrease in intraabdominal fat is suggested by studies in which peripheral leptin administration to rats was shown to selectively decrease visceral fat and improve insulin sensitivity (40); it is plausible that melatonin administration to the middle-aged rats in the curr…”
Influential
- Authors
- Barzilai, N., Wang, J., Massilon, D., Vuguin, P., Hawkins, M., & Rossetti, L.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Rossetti, L
- Venue
- Journal of Clinical Investigation
- Published
- 1997-12-15
- Volume
- 100
- Issue
- 12
- Pages
- 3105-3110
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508523
- OpenAlex
- W2152760501
- Cited by
- 335
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2022: 2 · 2021: 7 · 2020: 8 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 5 · 2015: 12 · 2014: 10 · 2013: 6 · 2012: 11
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Medical Research Council Canada
- National Institutes of Health
- Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-48321, DK20541, DK-45024)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- leptin, visceral fat, intra-abdominal fat, insulin action, insulin resistance, abdominal obesity, body fat distribution, hepatic glucose production, hepatic glucose uptake, hepatic gene expression, energy homeostasis, caloric restriction, hyperinsulinemia
- MeSH terms
- Adipose Tissue, Animals, Blood Glucose, Body Weight, Eating, Glucose, Insulin, Liver, Male, Proteins, Recombinant Proteins, Viscera, Gene Expression, Rats, Sprague-Dawley, Leptin, Mice, Rats
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