Leptin and the endocrine control of energy balance (original) (raw)

• Bray, G. A. Obesity: historical development of scientific and cultural ideas. Int. J. Obes. 14, 909–926 (1990).
  CAS PubMed Google Scholar
• Friedman, J. M. A war on obesity, not the obese. Science 299, 856–858 (2003).
  Article CAS PubMed Google Scholar
• Adolph, E. F. Urges to eat and drink in rats. Am. J. Physiol. 151, 110–125 (1947).
  Article CAS PubMed Google Scholar
• Kennedy, G. C. The role of depot fat in the hypothalamic control of food intake in the rat. Proc. R. Soc. Lond. 140, 578–596 (1953).
  CAS PubMed Google Scholar
• Neel, J. V. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress. Am. J. Hum. Genet. 14, 353–362 (1962).
  CAS PubMed PubMed Central Google Scholar
• Diamond, J. The double puzzle of diabetes. Nature 423, 599–602 (2003).
  Article CAS PubMed Google Scholar
• Speakman, J. R. A nonadaptive scenario explaining the genetic predisposition to obesity: the “predation release” hypothesis. Cell Metab. 6, 5–12 (2007).
  Article CAS PubMed Google Scholar
• Speakman, J. R. The evolution of body fatness: trading off disease and predation risk. J. Exp. Biol. 221(Suppl. 1), jeb167254 (2018).
  Article PubMed Google Scholar
• Ingalls, A. M., Dickie, M. M. & Snell, G. D. Obese, a new mutation in the house mouse. J. Hered. 41, 317–318 (1950).
  Article CAS PubMed Google Scholar
• Hummel, K. P., Dickie, M. M. & Coleman, D. L. Diabetes, a new mutation in the mouse. Science 153, 1127–1128 (1966).
  Article CAS PubMed Google Scholar
• Coleman, D. L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14, 141–148 (1978).
  Article CAS PubMed Google Scholar
• Zucker, L. M. & Zucker, T. F. Fatty, a new mutation in the rat. J. Hered. 52, 275–278 (1961).
  Article Google Scholar
• Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).
  Article CAS PubMed Google Scholar
• Hetherington, A. W. & Ranson, S. W. The spontaneous activity and food intake of rats with hypothalamic lesions. Am. J. Physiol. 136, 609–617 (1942).
  Article CAS Google Scholar
• Hervey, G. R. The effects of lesions in the hypothalamus in parabiotic rats. J. Physiol. (Lond.) 145, 336–352 (1959).
  Article CAS Google Scholar
• Coleman, D. L. & Hummel, K. P. Effects of parabiosis of normal with genetically diabetic mice. Am. J. Physiol. 217, 1298–1304 (1969).
  Article CAS PubMed Google Scholar
• Harris, R. B. S., Hervey, E., Hervey, G. R. & Tobin, G. Body composition of lean and obese Zucker rats in parabiosis. Int. J. Obes. 11, 275–283 (1987).
  CAS PubMed Google Scholar
• Coleman, D. L. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298 (1973).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Maffei, M. et al. Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc. Natl Acad. Sci. USA 92, 6957–6960 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).
  Article CAS PubMed Google Scholar
• Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R. & Burn, P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549 (1995).
  Article CAS PubMed Google Scholar
• Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).
  Article CAS PubMed Google Scholar
• Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).
  Article CAS PubMed Google Scholar
• Lee, G. H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).
  Article CAS PubMed Google Scholar
• Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, G. et al. Leptin receptor mutations in 129 db 3J /db 3J mice and NIH fa cp/fa cp rats. Mamm. Genome 8, 445–447 (1997).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Kowalski, T. J., Liu, S.-M., Leibel, R. L. & Chua, S. C. Jr. Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. Diabetes 50, 425–435 (2001).
  Article CAS PubMed Google Scholar
• Lord, G. M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998).
  Article CAS PubMed Google Scholar
• Mackey-Lawrence, N. M. & Petri, W. A. Jr. Leptin and mucosal immunity. Mucosal Immunol. 5, 472–479 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Reis, B. S. et al. Leptin receptor signaling in T cells is required for Th17 differentiation. J. Immunol. 194, 5253–5260 (2015).
  Article CAS PubMed Google Scholar
• Ghilardi, N. et al. Defective STAT signaling by the leptin receptor in diabetic mice. Proc. Natl Acad. Sci. USA 93, 6231–6235 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Bates, S. H. et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421, 856–859 (2003).
  Article CAS PubMed Google Scholar
• Gao, Q. et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc. Natl Acad. Sci. USA 101, 4661–4666 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Robertson, S. et al. Insufficiency of Janus kinase 2-autonomous leptin receptor signals for most physiologic leptin actions. Diabetes 59, 782–790 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006).
  Article CAS PubMed Google Scholar
• Hill, J. W. et al. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J. Clin. Invest. 118, 1796–1805 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Leshan, R. L., Greenwald-Yarnell, M., Patterson, C. M., Gonzalez, I. E. & Myers, M. G. Jr. Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. Nat. Med. 18, 820–823 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10, 739–743 (2004).
  Article CAS PubMed Google Scholar
• Bence, K. K. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12, 917–924 (2006).
  Article CAS PubMed Google Scholar
• Björnholm, M. et al. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J. Clin. Invest. 117, 1354–1360 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Bjørbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. & Flier, J. S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 (1998).
  Article PubMed Google Scholar
• Friedman, J. M. The alphabet of weight control. Nature 385, 119–120 (1997).
  Article CAS PubMed Google Scholar
• Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530–532 (1995).
  Article CAS PubMed Google Scholar
• Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).
  Article CAS PubMed Google Scholar
• Elias, C. F. et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786 (1999).
  Article CAS PubMed Google Scholar
• Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991 (2004).
  Article CAS PubMed Google Scholar
• Gao, Y. et al. TrpC5 mediates acute leptin and serotonin effects via Pomc neurons. Cell Rep. 18, 583–592 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Smith, M. A. et al. Calcium channel CaV2.3 subunits regulate hepatic glucose production by modulating leptin-induced excitation of arcuate pro-opiomelanocortin neurons. Cell Rep. 25, 278–287.e4 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Caron, A. et al. POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels. eLife 7, e33710 (2018).
  Article PubMed PubMed Central Google Scholar
• Xu, J. et al. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556, 505–509 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Baver, S. B. et al. Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J. Neurosci. 34, 5486–5496 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Takahashi, K. A. & Cone, R. D. Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-related protein neurons. Endocrinology 146, 1043–1047 (2005).
  Article CAS PubMed Google Scholar
• Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D. & Ashford, M. L. J. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–525 (1997).
  Article CAS PubMed Google Scholar
• Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).
  Article CAS PubMed Google Scholar
• Bouret, S. G., Draper, S. J. & Simerly, R. B. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110 (2004).
  Article CAS PubMed Google Scholar
• Wu, Q., Boyle, M. P. & Palmiter, R. D. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137, 1225–1234 (2009).
  Article PubMed PubMed Central Google Scholar
• Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Betley, J. N. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Domingos, A. I. et al. Leptin regulates the reward value of nutrient. Nat. Neurosci. 14, 1562–1568 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, X.-Y., Kim, C. S., Frazer, A. & Zhang, W. Leptin: a potential novel antidepressant. Proc. Natl Acad. Sci. USA 103, 1593–1598 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Scott, M. M. et al. Leptin targets in the mouse brain. J. Comp. Neurol. 514, 518–532 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Leshan, R. L., Björnholm, M., Münzberg, H. & Myers, M. G. Jr. Leptin receptor signaling and action in the central nervous system. Obesity (Silver Spring) 14(Suppl. 5), 208S–212S (2006).
  Article CAS Google Scholar
• Williams, K. W., Zsombok, A. & Smith, B. N. Rapid inhibition of neurons in the dorsal motor nucleus of the vagus by leptin. Endocrinology 148, 1868–1881 (2007).
  Article CAS PubMed Google Scholar
• Williams, K. W. & Smith, B. N. Rapid inhibition of neural excitability in the nucleus tractus solitarii by leptin: implications for ingestive behaviour. J. Physiol. (Lond.) 573, 395–412 (2006).
  Article CAS Google Scholar
• Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).
  Article CAS PubMed Google Scholar
• Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Leinninger, G. M. et al. Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab. 14, 313–323 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Andermann, M. L. & Lowell, B. B. Toward a wiring diagram understanding of appetite control. Neuron 95, 757–778 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Peng, Y. et al. A general method for insertion of functional proteins within proteins via combinational selection of permissive junctions. Chem. Biol. 22, 1134–1143 (2015).
  Article CAS PubMed Google Scholar
• Banks, W. A. & Farrell, C. L. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am. J. Physiol. Endocrinol. Metab. 285, E10–E15 (2003).
  Article CAS PubMed Google Scholar
• Balland, E. et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 19, 293–301 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Yoo, S., Cha, D., Kim, D. W., Hoang, T. V. & Blackshaw, S. Tanycyte-independent control of hypothalamic leptin signaling. Front. Neurosci. 13, 240 (2019).
  Article PubMed PubMed Central Google Scholar
• Yoo, S. et al. Ablation of tanycytes of the arcuate nucleus and median eminence increases visceral adiposity and decreases insulin sensitivity in male mice. Preprint at bioRxiv https://doi.org/10.1101/637587 (2019).
• Ceccarini, G. et al. PET imaging of leptin biodistribution and metabolism in rodents and primates. Cell Metab. 10, 148–159 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Tinbergen, N. The Hierarchical Organization of Nervous Mechanisms Underlying Instinctive Behaviour. Symp. Soc. Exp. Biol. 4, 305–312 (1950).
  Google Scholar
• Sherrington, C. S. The Integrative Action of the Nervous System (Yale University Press, 1906).
• Burke, R. E. Sir Charles Sherrington’s the integrative action of the nervous system: a centenary appreciation. Brain 130, 887–894 (2007).
  Article PubMed Google Scholar
• Han, W. et al. Integrated control of predatory hunting by the central nucleus of the amygdala. Cell 168, 311–324.e18 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Miroschnikow, A. et al. Convergence of monosynaptic and polysynaptic sensory paths onto common motor outputs in a Drosophila feeding connectome. eLife 7, e40247 (2018).
  Article PubMed PubMed Central Google Scholar
• Barash, I. A. et al. Leptin is a metabolic signal to the reproductive system. Endocrinology 137, 3144–3147 (1996).
  Article CAS PubMed Google Scholar
• Chehab, F. F., Lim, M. E. & Lu, R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat. Genet. 12, 318–320 (1996).
  Article CAS PubMed Google Scholar
• Chehab, F. F., Mounzih, K., Lu, R. & Lim, M. E. Early onset of reproductive function in normal female mice treated with leptin. Science 275, 88–90 (1997).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).
  Article CAS PubMed Google Scholar
• Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).
  Article CAS PubMed Google Scholar
• Singh, A. et al. Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels. Proc. Natl Acad. Sci. USA 106, 13100–13105 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Clemmensen, C. et al. Gut-brain cross-talk in metabolic control. Cell 168, 758–774 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Mayer, E. A. Gut feelings: the emerging biology of gut-brain communication. Nat. Rev. Neurosci. 12, 453–466 (2011).
  Article CAS PubMed Google Scholar
• Berthoud, H. R. Vagal and hormonal gut-brain communication: from satiation to satisfaction. Neurogastroenterol. Motil. 20(Suppl. 1), 64–72 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ravussin, Y. et al. Evidence for a non-leptin system that defends against weight gain in overfeeding. Cell Metab. 28, 289–299.e5 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Jansson, J. O. et al. Body weight homeostat that regulates fat mass independently of leptin in rats and mice. Proc. Natl Acad. Sci. USA 115, 427–432 (2018).
  Article CAS PubMed Google Scholar
• Ioffe, E., Moon, B., Connolly, E. & Friedman, J. M. Abnormal regulation of the leptin gene in the pathogenesis of obesity. Proc. Natl Acad. Sci. USA 95, 11852–11857 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. & Goldstein, J. L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76 (1999).
  Article CAS PubMed Google Scholar
• Dallner, O. S. et al. Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity. Nat. Med. 25, 507–516 (2019).
  Article CAS PubMed Google Scholar
• Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).
  Article CAS PubMed Google Scholar
• Barsh, G. S., Farooqi, I. S. & O’Rahilly, S. Genetics of body-weight regulation. Nature 404, 644–651 (2000).
  Article CAS PubMed Google Scholar
• Wunderlich, C. M., Hövelmeyer, N. & Wunderlich, F. T. Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. JAK-STAT 2, e23878 (2013).
  Article PubMed PubMed Central Google Scholar
• Reed, A. S. et al. Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 59, 894–906 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bjorbak, C. et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J. Biol. Chem. 275, 40649–40657 (2000).
  Article CAS PubMed Google Scholar
• Ottaway, N. et al. Diet-induced obese mice retain endogenous leptin action. Cell Metab. 21, 877–882 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Enriori, P. J. et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 5, 181–194 (2007).
  Article CAS PubMed Google Scholar
• Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257–7262 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, J., Lee, J., Salazar Hernandez, M. A., Mazitschek, R. & Ozcan, U. Treatment of obesity with celastrol. Cell 161, 999–1011 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Müller, T. D. et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci. 18, 383–393 (2012).
  Article PubMed CAS Google Scholar
• Clemmensen, C. et al. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes 63, 1422–1427 (2014).
  Article CAS PubMed Google Scholar
• Mark, A. L. Selective leptin resistance revisited. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R566–R581 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Pessin, J. E. & Saltiel, A. R. Signaling pathways in insulin action: molecular targets of insulin resistance. J. Clin. Invest. 106, 165–169 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Boucher, J., Kleinridders, A. & Kahn, C. R. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 6, a009191 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Knight, Z. A., Hannan, K. S., Greenberg, M. L. & Friedman, J. M. Hyperleptinemia is required for the development of leptin resistance. PLoS One 5, e11376 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Nectow, A. R. et al. Identification of a brainstem circuit controlling feeding. Cell 170, 429–442.e11 (2017).
  Article CAS PubMed Google Scholar
• Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).
  Article CAS PubMed Google Scholar
• Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999).
  Article CAS PubMed Google Scholar
• Licinio, J. et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behaviour in leptin-deficient adults. Proc. Natl Acad. Sci. USA 101, 4531–4536 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Farooqi, I. S. et al. Leptin regulates striatal regions and human eating behaviour. Science 317, 1355 (2007).
  Article CAS PubMed Google Scholar
• Rosenbaum, M. et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579–3586 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Ozata, M., Ozdemir, I. C. & Licinio, J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J. Clin. Endocrinol. Metab. 84, 3686–3695 (1999).
  Article CAS PubMed Google Scholar
• Oral, E. A. et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578 (2002).
  Article CAS PubMed Google Scholar
• Yu, X., Park, B. H., Wang, M. Y., Wang, Z. V. & Unger, R. H. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc. Natl Acad. Sci. USA 105, 14070–14075 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Cochran, E. et al. Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome. J. Clin. Endocrinol. Metab. 89, 1548–1554 (2004).
  Article CAS PubMed Google Scholar
• Brown, R. J. et al. Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy. J. Clin. Invest. 128, 3504–3516 (2018).
  Article PubMed PubMed Central Google Scholar
• Brown, R. J. et al. Effects of metreleptin in pediatric patients with lipodystrophy. J. Clin. Endocrinol. Metab. 102, 1511–1519 (2017).
  Article PubMed PubMed Central Google Scholar
• Lee, H. L. et al. Effects of metreleptin on proteinuria in patients with lipodystrophy. J. Clin. Endocrinol. Metab. https://doi.org/10.1210/jc.2019-00200 (2019).
  Article Google Scholar
• Asilmaz, E. et al. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J. Clin. Invest. 113, 414–424 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Welt, C. K. et al. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987–997 (2004).
  Article CAS PubMed Google Scholar
• Chou, S. H. et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc. Natl Acad. Sci. USA 108, 6585–6590 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Köpp, W. et al. Low leptin levels predict amenorrhea in underweight and eating disordered females. Mol. Psychiatry 2, 335–340 (1997).
  Article PubMed Google Scholar
• Hebebrand, J. et al. Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration. Mol. Psychiatry 2, 330–334 (1997).
  Article CAS PubMed Google Scholar
• Sienkiewicz, E. et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 60, 1211–1221 (2011).
  Article CAS PubMed Google Scholar
• Ravussin, E. et al. Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat. Med. 3, 238–240 (1997).
  Article CAS PubMed Google Scholar
• Heymsfield, S. B. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. J. Am. Med. Assoc. 282, 1568–1575 (1999).
  Article CAS Google Scholar
• Depaoli, A., Long, A., Fine, G.M., Stewart, M. & O’Rahilly, S. Efficacy of metreleptin for weight loss in overweight and obese adults with low leptin levels. Diabetes https://doi.org/10.2337/db18-296-LB (2018).
  Article Google Scholar
• Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996).
  Article CAS PubMed Google Scholar
• Kilpeläinen, T. O. et al. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat. Commun. 7, 10494 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Dhurandhar, E. J. The food-insecurity obesity paradox: A resource scarcity hypothesis. Physiol. Behav. 162, 88–92 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Prentice, A. M., Hennig, B. J. & Fulford, A. J. Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release? Int. J. Obes. (Lond). 32, 1607–1610 (2008).
  Article CAS Google Scholar
• Diamond, J. M. Guns, Germs, and Steel: the Fates of Human Societies (W. W. Norton, 1997).
• 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).
  CAS PubMed Google Scholar
• Clee, S. M. & Attie, A. D. The genetic landscape of type 2 diabetes in mice. Endocr. Rev. 28, 48–83 (2007).
  Article CAS PubMed Google Scholar
• Friedman, J. M. Obesity is genetic. Newsweek (9 September 2009).
• Friedman, J. M. Modern science versus the stigma of obesity. Nat. Med. 10, 563–569 (2004).
  Article CAS PubMed Google Scholar
• Park, H. K. & Ahima, R. S. Leptin signaling. F1000Prime Rep. 6, 73 (2014).
  PubMed PubMed Central Google Scholar
• Diamond, J. M. Diabetes running wild. Nature 357, 362–363 (1992).
  Article CAS PubMed Google Scholar
• Mayer-Davis, E. J. et al. Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012. N. Engl. J. Med. 376, 1419–1429 (2017).
  Article PubMed PubMed Central Google Scholar
• Hawkes, K. Human longevity: the grandmother effect. Nature 428, 128–129 (2004).
  Article CAS PubMed Google Scholar