Obese people, who are already subject to adverse health effects, are additionally victimized by a social stigma predicated on the Hippocratic nostrum that weight can be controlled by 'deciding' to eat less and exercise more. This simplistic notion is at odds with substantial scientific evidence illuminating a precise and powerful biologic system that maintains body weight within a relatively narrow range. Voluntary efforts to reduce weight are resisted by potent compensatory biologic responses. This article will review some of this evidence, together with promising avenues of research. Further progress in understanding and treating obesity will come not from repetition of anachronistic preconceptions but rather from the rigorous scientific approach that has driven advances in so many other areas of medicine.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
L-PGDS-produced PGD2 in premature, but not in mature, adipocytes increases obesity and insulin resistance
Scientific Reports Open Access 13 February 2019
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Bray, G.A. Obesity: Historical development of scientific and cultural ideas. Int. J. Obes. 14, 909–926 (1990).
Buchwald, H. & Knatterud, M.E. Morbid obesity: perceptions of character and comorbidities in Falstaff. Obes. Surg. 10, 402–408 (2000).
Allison, D. et al. The heritability of body mass index among an international sample of monozygotic twins reared apart. Int. J. Obes. Relat. Metab. Disord. 20, 501–506 (1996).
Stunkard, A.J., Harris, J.R., Pedersen, N.L. & McClearn, G.E. The body-mass index of twins who have been reared apart. N. Engl. J. Med. 322, 1483–1487 (1990).
Stunkard, A.J., Foch, T.T. & Hrubec, Z. A twin study of human obesity. J. Am. Med. Assoc. 256, 51–54 (1986).
Friedman, J.M. A war on obesity, not the obese. Science 299, 856–858 (2003).
Flier, J.S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004).
O'Rahilly, S., Farooqi, I.S., Yeo, G. & Challis, B.G. Minireview: Human obesity—lessons from monogenic disorders. Endocrinology 144, 3757–3764 (2003).
Leibel, R.L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621–628 (1995).
Wadden, T.A. et al. Short- and long-term changes in serum leptin dieting obese women: effects of caloric restriction and weight loss. J. Clin. Endocrinol. Metab. 83, 214–218 (1998).
Wadden, T.A. Treatment of obesity by moderate and severe caloric restriction. Results of clinical research trials. Ann. Intern. Med. 119, 688–693 (1993).
Farooqi, I. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999).
Farooqi, I.S. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110, 1093–1103 (2002).
Flegal, K.M., Carroll, M.D., Ogden, C.L. & Johnson, C.L. Prevalence and trends in obesity among US adults, 1999-2000. J. Am. Med. Assoc. 288, 1723–1727 (2002).
Harris, T. et al. Body mass index and mortality among nonsmoking older persons: the Framingham Heart Study. J. Am. Med. Assoc. 259, 1520–1524 (1988).
Kopelman, P.G. Obesity as a medical problem. Nature 404, 635–643 (2000).
Hetherington, A.W. & Ranson, S.W. The spontaneous activity and food intake of rats with hypothalamic lesions. Am. J. Physiol. 136, 609–617 (1942).
Kandel, E.R., Schwartz, J.H. & Jessell, T. Principles of Neural Science, 998–1003 (McGraw-Hill, New York, 2000).
Friedman, J.M. & Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).
Montague, C.T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).
Farooqi, I. et al. Partial leptin deficiency and human adiposity. Nature 414, 34–35 (2001).
Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1, 1155–1161 (1995).
Ahima, R.S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).
Shimomura, I., Hammer, R., Ikemoto, S., Brown, M. & Goldstein, J. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76 (1999).
Oral, E.A. et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578 (2002).
Oral, E.A. et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J. Clin. Endocrinol. Metab. 87, 3110–3117 (2002).
Petersen, K.F. et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109, 1345–1350 (2002).
Heymsfield, S. et al. Recombinant leptin for weight loss in obese and lean adults. J. Am. Med. Assoc. 282, 1568–1575 (1999).
Halaas, J.L. et al. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl. Acad. Sci. USA 94, 8878–8883 (1997).
Minokoshi, Y. et al. Leptin stimulates fatty acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002).
Fei, H. et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc. Natl. Acad. Sci. USA 94, 7001–7005 (1997).
Glazer, G. Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety. Arch. Intern. Med. 161, 1814–1824 (2001).
Heisler, L.K. et al. Activation of central melanocortin pathways by fenfluramine. Science 297, 609–611 (2002).
Seeley, R.J. et al. Melanocortin receptors in leptin effects. Nature 390, 349 (1997).
Erickson, J.C., Clegg, K.E. & Palmiter, R.D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415–418 (1996).
Obici, S. & Rossetti, L. Minireview: Nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 144, 5172–5178 (2003).
Niswender, K.D. et al. Key enzymes in leptin-induced anorexia. Nature 413, 794–795 (2001).
Li, C. & Friedman, J. Leptin receptor activation of SH2 domain protein tyrosone phosphatase 2 modulates ob receptor signal transduction. Proc. Natl. Acad. Sci. USA 96, 9677–9682 (1999).
Zhao, A.Z., Huan, J.N., Gupta, S.K., Pal, R. & Sahu, A. A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding. Nat. Neurosci. 5, 727–728 (2002).
Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 14, 95–97 (1996).
Bates, S.H. et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421, 856–859 (2003).
Zabolothy, J.M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).
Bjorbaek, C., Elmquist, J.K., Frantz, J.D., Shoelson, S.E. & Flier, J.S. Identification of SOC-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 (1998).
Yeo, G. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111–112 (1998).
Pinto, S. et al. Rapid re-wiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).
West, D.B., Boozer, C.N., Moody, D.L. & Atkinson, R.L. Dietary obesity in nine inbred mouse strains. Am. J. Physiol. 262, R1025–R1032 (1992).
Ogus, S., Ke, Y., Qiu, J., Wang, B. & Chehab, F.F. Hyperleptinemia precipitates diet-induced obesity in transgenic mice overexpressing leptin. Endocrinology 144, 2865–2869 (2003).
Fulton, S., Woodside, B. & Shizgal, P. Modulation of brain reward circuitry by leptin. Science 287, 125–128 (2000).
Saper, C.B., Chou, T.C. & Elmquist, J.K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002).
DeFalco, J. et al. Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus. Science 291, 2608–2613 (2001).
Schwartz, M.W., Peskind, E., Raskind, M., Boyko, E.J. & Porte, D. Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat. Med. 2, 589–593 (1996).
Caro, J.F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).
Banks, W.A. & Farrell, C.L. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. J. Physiol. 285, E10–E15 (2003).
Li, C., Ioffe, E., Fidahusein, N., Connolly, E. & Friedman, J.M. Absence of soluble leptin receptor in plasma from dbPas/dbPas and other db/db mice. J. Biol. Chem. 273, 10078–10082 (1998).
Weintraub, M., Hasday, J.D., Mushlin, A.I. & Lockwood, D.H. A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch. Intern. Med. 144, 1143–1148 (1984).
Heal, D.J., Cheetham, S.C., Prow, M.R., Martin, K.F. & Buckett, W.R. A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents. Br. J. Pharmacol. 125, 301–308 (1998).
Tecott, L.H. et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374, 542–546 (1995).
Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).
Lavoisier, A.L. & DeLaplace, P.S. Memoir on heat; Read to the Royal Academy of Sciences, 28 June 1783. Obes. Res. 2, 189–203 (1994).
Rubner, M. Die Quelle der thierischen Warme. Z. Biol. 30, 73–142 (1894).
Weigle, D.S. Appetite and the regulation of body composition. FASEB J. 8, 302–310 (1994).
Allison, D.B., Heshka, S., Sepulveda, D. & Heymsfield, S.B. Counting calories—caveat emptor. J. Am. Med. Assoc. 270, 1454–1456 (1993).
Ravussin, E. et al. Reduced rate of energy expenditure as a risk factor for body-weight gain. N. Engl. J. Med. 318, 467–472 (1988).
Bouchard, C. et al. The response to long-term overfeeding in identical twins. N. Engl. J. Med. 322, 1477–1482 (1990).
Levine, J.A., Eberhardt, N.L. & Jensen, M.D. Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science 283, 212–214 (1999).
Brolin, R.E. Bariatric surgery and long-term control of morbid obesity. J. Am. Med. Assoc. 288, 2793–2796 (2002).
Halaas, J.L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).
Bultman, S.J., Michaud, E.J. & Woychik, R.P. Molecular characterization of the mouse agouti locus. Cell 71, 1195–1204 (1992).
Smith, S. et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT. Nat. Genet. 25, 87–90 (2000).
Cohen, P. et al. Role for stearoyl-CoA desaturase-1 in leptin mediated weight loss. Science 297, 240–243 (2002).
Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).
Wang, Y.X. et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).
Bachman, E.S. et al. βAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297, 843–845 (2002).
Jackson, R.S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303–306 (1997).
Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155–157 (1998).
Barsh, G.S., Farooqi, I.S. & O'Rahilly, S. Genetics of body-weight regulation. Nature 404, 644–651 (2000).
Neel, J.V. Diabetes mellitus: A “thrifty” genotype rendered detrimental by “progress”? Am. J. Hum. Genet. 14, 353–362 (1962).
Tuomilehto, J. et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344, 1343–1350 (2001).
The author thanks E. Ravussin, Bruce Schneider and S. Heymesfield for critical comments, and S. Korres for assistance in preparing this manuscript. This work was supported by a grant from the US National Institute of Diabetes and Digestive and Kidney Diseases. The author is an inventor listed on the patent for leptin and might receive a portion of the royalties, through a Rockefeller University licensing agreement with Amgen, should leptin become a commercial product.
Rights and permissions
About this article
Cite this article
Friedman, J. Modern science versus the stigma of obesity. Nat Med 10, 563–569 (2004). https://doi.org/10.1038/nm0604-563
This article is cited by
Adherence to Lifelines Diet Score (LLDS) is associated with better sleep quality in overweight and obese women
Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity (2021)
Effect of short-term intake of four sweeteners on feed intake, solution consumption and neurotransmitters release on mice
Journal of Food Science and Technology (2021)
Prolonged-release pirfenidone prevents obesity-induced cardiac steatosis and fibrosis in a mouse NASH model
Cardiovascular Drugs and Therapy (2021)
Obesity, the most common comorbidity in SARS-CoV-2: is leptin the link?
International Journal of Obesity (2020)
Leptin and the endocrine control of energy balance
Nature Metabolism (2019)