Leptin applications in 2015: What have we learned about leptin and obesity?

Current Opinion in Endocrinology, Diabetes and Obesity

Volumn 22, Issue 5, 2015, Pages 353-359

  Farr, Olivia M ^a   Gavrieli, Anna ^a,b   Mantzoros, Christos S ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

Author keywords

hypoleptinemia; leptin; leptin resistance; lipodystrophy; obesity

Indexed keywords

LEPTIN; LEPTIN RECEPTOR;

CALORIC INTAKE; ENERGY EXPENDITURE; HUMAN; HYPERLEPTINEMIA; LEPTIN DEFICIENCY; LIPOATROPHY; LIPODYSTROPHY; LIPOHYPERTROPHY; NONHUMAN; OBESITY; REVIEW; SUBSTITUTION THERAPY; WEIGHT REDUCTION; ANIMAL; DEFICIENCY; GENETICS; METABOLISM;

ANIMALS; HUMANS; LEPTIN; LIPODYSTROPHY; OBESITY;

EID: 84952984418     PISSN: 1752296X     EISSN: 17522978     Source Type: Journal    
DOI: 10.1097/MED.0000000000000184     Document Type: Review

References (105)

1. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425-432.
2. Chan JL, Heist K, DePaoli AM, et al. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-Term starvation in healthy men. J Clin Invest 2003; 111:1409-1421.
3. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern Med 2010; 152:93-100.
4. Broberger C, Johansen J, Johansson C, et al. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-Treated mice. Proc Natl Acad Sci U S A 1998; 95:15043-15048.
5. Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88:131-141.
6. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci 2005; 8:571-578.
7. Dalamaga M, Chou SH, Shields K, et al. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab 2013; 18:29-42.
8. Strobel A, Issad T, Camoin L, et al. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998; 18:213-215.
9. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341:879-884.
10. Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011; 108:6585-6590.
11. Audi L, Mantzoros CS, Vidal-Puig A, et al. Leptin in relation to resumption of menses in women with anorexia nervosa. Mol Psychiatry 1998; 3:544-547.
12. Aronis KN, Kilim H, Chamberland JP, et al. Preadipocyte factor-1 levels are higher in women with hypothalamic amenorrhea and are associated with bone mineral content and bone mineral density through a mechanism independent of leptin. J Clin Endocrinol Metab 2011; 96:E1634-1639.
13. Frank S, Heni M, Moss A, et al. Long-Term stabilization effects of leptin on brain functions in a leptin-Deficient patient. PLoS One 2013; 8:e65893.
14. Frank S, Heni M, Moss A, et al. Leptin therapy in a congenital leptin-Deficient patient leads to acute and long-Term changes in homeostatic, reward, and food-related brain areas. J Clin Endocrinol Metab 2011; 96:E1283-1287.
15. Matarese G, La Rocca C, Moon HS, et al. Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci U S A 2013; 110:E818-827.
16. Lu XY, Kim CS, Frazer A, Zhang W. Leptin: a potential novel antidepressant. Proc Natl Acad Sci U S A 2006; 103:1593-1598.
17. Ge JF, Qi CC, Zhou JN. Imbalance of leptin pathway and hypothalamus synaptic plasticity markers are associated with stress-induced depression in rats. Behav Brain Res 2013; 249:38-43.
18. Johnston JM, Greco SJ, Hamzelou A, et al. Repositioning leptin as a therapy for Alzheimer?s disease. Therapy 2011; 8:481-490.
19. Koch CE, Lowe C, Pretz D, et al. High fat diet induces leptin resistance. J Neuroendocrinol 2014; 26:58-67.
20. Bereiter DA, Jeanrenaud B. Altered neuroanatomical organization in the central nervous system of the genetically obese (ob/ob) mouse. Brain Res 1979; 165:249-260.
21. Steppan CM, Swick AG. A role for leptin in brain development. Biochem Biophys Res Commun 1999; 256:600-602.
22. Vannucci SJ, Gibbs EM, Simpson IA. Glucose utilization and glucose transporter proteins GLUT-1 and GLUT-3 in brains of diabetic (db/db) mice. Am J Physiol 1997; 272:E267-274.
23. Hashimoto R, Matsumoto A, Udagawa J, et al. Effect of leptin administration on myelination in ob/ob mouse cerebrum after birth. Neuroreport 2013; 24:22-29.
24. Bluher S, Shah S, Mantzoros CS. Leptin deficiency: clinical implications and opportunities for therapeutic interventions. J Investig Med 2009; 57:784-788.
25. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387:903-908.
26. Gill R, Cheung YH, Shen Y, et al. Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. Obesity (Silver Spring) 2014; 22:576-584.
27. Saeed S, Bonnefond A, Manzoor J, et al. Novel LEPR mutations in obese Pakistani children identified by PCR-based enrichment and next generation sequencing. Obesity (Silver Spring) 2014; 22:1112-1117.
28. Huvenne H, Le Beyec J, Pepin D, et al. Seven novel deleterious LEPR mutations found in early-onset obesity: a Deltaexon 6-8 shared by subjects from Reunion Island, France suggests a founder effect. J Clin Endocrinol Metab 2015; 100:E757-E766.
29. Farooqi IS, Orahilly S. 20 years of leptin: human disorders of leptin action. J Endocrinol 2014; 223:T63-T70.
30. Licinio J, Caglayan S, Ozata M, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptindeficient adults. Proc Natl Acad Sci U S A 2004; 101:4531-4536.
31. Farooqi IS, Bullmore E, Keogh J, et al. Leptin regulates striatal regions and human eating behavior. Science 2007; 317:1355.
32. Baicy K, London ED, Monterosso J, et al. Leptin replacement alters brain response to food cues in genetically leptin-Deficient adults. Proc Natl Acad Sci U S A 2007; 104:18276-18279.
33. Jimerson DC, Mantzoros C, Wolfe BE, Metzger ED. Decreased serum leptin in bulimia nervosa. J Clin Endocrinol Metab 2000; 85:4511-4514.
34. Laughlin GA, Dominguez CE, Yen SS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1998; 83:25-32.
35. Laughlin GA, Yen SS. Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab 1997; 82:318-321.
36. Miller KK, Parulekar MS, Schoenfeld E, et al. Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. J Clin Endocrinol Metab 1998; 83:2309-2312.
37. Reindollar RH, Novak M, Tho SP, McDonough PG. Adult-onset amenorrhea: a study of 262 patients. Am J Obstet Gynecol 1986; 155:531-543.
38. Berga SL, Daniels TL, Giles DE. Women with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrations. Fertil Steril 1997; 67:1024-1030.
39. Misra M, Miller KK, Bjornson J, et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2003; 88:5615-5623.
40. Warren MP, Stiehl AL. Exercise and female adolescents: effects on the reproductive and skeletal systems. J Am Med Womens Assoc 1999; 54:115-120.
41. Foo JP, Hamnvik OP, Mantzoros CS. Optimizing bone health in anorexia nervosa and hypothalamic amenorrhea: new trials and tribulations. Metabolism 2012; 61:899-905.
42. Farr OM, Fiorenza C, Papageorgiou P, et al. Leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin-sensitive subjects without altering brain structure. J Clin Endocrinol Metab 2014; 99:E2529-2538.
43. Moon HS, Chamberland JP, Diakopoulos KN, et al. Leptin and amylin act in an additive manner to activate overlapping signaling pathways in peripheral tissues: in vitro and ex vivo studies in humans. Diabetes Care 2011; 34:132-138.
44. Nagy GS, Tsiodras S, Martin LD, et al. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis 2003; 36:795-802.
45. Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and HIV-Associated lipodystrophy. Metabolism 2015; 64:47-59.
46. Rodriguez AJ, Neeman T, Giles AG, et al. Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a metaanalysis into the effects of leptin on metabolic and hepatic endpoints. Arq Bras Endocrinol Metab 2014; 58:783-797.
47. Yamauchi T, Kamon J, Waki H, et al. The fat-Derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7:941-946.
48. Shimomura I, Hammer RE, Ikemoto S, et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999; 401:73-76.
49. Moon HS, Dalamaga M, Kim SY, et al. Leptin?s role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr Rev 2013; 34:377-412.
50. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346:570-578.
51. Beltrand J, Beregszaszi M, Chevenne D, et al. Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy. Pediatrics 2007; 120:e291-E296.
52. Beltrand J, Lahlou N, Le Charpentier T, et al. Resistance to leptin-replacement therapy in Berardinelli-Seip congenital lipodystrophy: an immunological origin. Eur J Endocrinol 2010; 162:1083-1091.
53. Chan JL, Lutz K, Cochran E, et al. Clinical effects of long-Term metreleptin treatment in patients with lipodystrophy. Endocr Pract 2011; 17:922-932.
54. Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 2010; 53:27-35.
55. Ebihara K, Kusakabe T, Hirata M, et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 2007; 92:532-541.
56. Javor ED, Cochran EK, Musso C, et al. Long-Term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 2005; 54:1994-2002.
57. Moran SA, Patten N, Young JR, et al. Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 2004; 53:513-519.
58. Oral EA, Ruiz E, Andewelt A, et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 2002; 87:3110-3117.
59. Park JY, Chong AY, Cochran EK, et al. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of longterm leptin therapy. J Clin Endocrinol Metab 2008; 93:26-31.
60. Park JY, Javor ED, Cochran EK, et al. Long-Term efficacy of leptin replacement in patients with Dunnigan-Type familial partial lipodystrophy. Metabolism 2007; 56:508-516.
61. Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109:1345-1350.
62. Safar Zadeh E, Lungu AO, Cochran EK, et al. The liver diseases of lipodystrophy: the long-Term effect of leptin treatment. J Hepatol 2013; 59:131-137.
63. Simha V, Subramanyam L, Szczepaniak L, et al. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab 2012; 97:785-792.
64. Musso C, Cochran E, Javor E, et al. The long-Term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 2005; 54:255-263.
65. Aotani D, Ebihara K, Sawamoto N, et al. Functional magnetic resonance imaging analysis of food-related brain activity in patients with lipodystrophy undergoing leptin replacement therapy. J Clin Endocrinol Metab 2012; 97:3663-3671.
66. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384:766-781.
67. Mehta T, Fontaine KR, Keith SW, et al. Obesity and mortality: are the risks declining?. Evidence from multiple prospective studies in the United States. Obes Rev 2014; 15:619-629.
68. Chou K, Perry CM. Metreleptin: first global approval. Drugs 2013; 73:989-997.
69. Yazdi FT, Clee SM, Meyre D. Obesity genetics in mouse and human: back and forth, and back again. Peer J 2015; 3:e856.
70. Dubern B, Clement K. Leptin and leptin receptor-related monogenic obesity. Biochimie 2012; 94:2111-2115.
71. Lonnqvist F, Arner P, Nordfors L, Schalling M. Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med 1995; 1:950-953.
72. Hamilton BS, Paglia D, Kwan AY, Deitel M. Increased obese mRNA expression in omental fat cells from massively obese humans. Nat Med 1995; 1:953-956.
73. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334:292-295.
74. Ravussin Y, LeDuc CA, Watanabe K, et al. Effects of chronic leptin infusion on subsequent body weight and composition in mice: can body weight set point be reset?. Mol Metab 2014; 3:432-440.
75. Banks WA. Role of the blood-brain barrier in the evolution of feeding and cognition. Ann N Y Acad Sci 2012; 1264:13-19.
76. Wauman J, Tavernier J. Leptin receptor signaling: pathways to leptin resistance. Front Biosci (Landmark Ed) 2011; 16:2771-2793.
77. Jung CH, Kim MS. Molecular mechanisms of central leptin resistance in obesity. Arch Pharm Res 2013; 36:201-207.
78. Sahu M, Anamthathmakula P, Sahu A. Phosphodiesterase-3B-cAMP pathway of leptin signalling in the hypothalamus is impaired during the development of diet-induced obesity in FVB/N mice. J Neuroendocrinol 2015; 27:293-302.
79. Tung YC, Gulati P, Liu CH, et al. FTO is necessary for the induction of leptin resistance by high-fat feeding. Mol Metab 2015; 4:287-298.
80. Lee E, Jung DY, Kim JH, et al. Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. FASEB J 2015. [Epub ahead of print] The authors found that a lack of TRPV1 increases obesity and insulin resistance with high fat diets and with aging.
81. Hosoi T, Matsuzaki S, Miyahara T, et al. Possible involvement of 15-Deoxy-Delta(12,14)-prostaglandin J2 in the development of leptin resistance. J Neurochem 2015; 133:343-351.
82. Litwak SA, Wilson JL, Chen W, et al. Estradiol prevents fat accumulation and overcomes leptin resistance in female high-fat diet mice. Endocrinology 2014; 155:4447-4460.
83. Long L, Toda C, Jeong JK, et al. PPARgamma ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding. J Clin Invest 2014; 124:4017-4027.
84. Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269:540-543.
85. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341:879-884.
86. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, doseescalation trial. JAMA 1999; 282:1568-1575.
87. Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metab Clin Exp 2015; 64:146-156.
88. Shetty GK, Matarese G, Magkos F, et al. Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. Eur J Endocrinol 2011; 165:249-254.
89. Knuth ND, Johannsen DL, Tamboli RA, et al. Metabolic adaptation following massive weight loss is related to the degree of energy imbalance and changes in circulating leptin. Obesity 2014; 22:2563-2569.
90. McNeil J, Schwartz A, Rabasa-Lhoret R, et al. Changes in leptin and peptide YY do not explain the greater-Than-predicted decreases in resting energy expenditure after weight loss. J Clin Endocrinol Metab 2015; 100:E443-E452.
91. Lecoultre V, Ravussin E, Redman LM. The fall in leptin concentration is a major determinant of the metabolic adaptation induced by caloric restriction independently of the changes in leptin circadian rhythms. J Clin Endocrinol Metab 2011; 96:E1512-1516.
92. Rosenbaum M, Sy M, Pavlovich K, et al. Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Investig 2008; 118:2583-2591.
93. Rosenbaum M, Goldsmith R, Bloomfield D, et al. Low-Dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Investig 2005; 115:3579-3586.
94. Hinkle W, Cordell M, Leibel R, et al. Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans. PLoS One 2013; 8:e59114.
95. Kissileff HR,ThorntonJC, Torres MI, et al. Leptin reverses declines in satiation in weight-reduced obese humans. Am J Clin Nutr 2012; 95:309-317.
96. Conroy R, Febres G, McMahon DJ, et al. Recombinant human leptin does not alter gut hormone levels after gastric bypass but may attenuate sweet cravings. Int J Endocrinol 2014; 2014:120286.
97. Korner J, Conroy R, Febres G, et al. Randomized double-blind placebocontrolled study of leptin administration after gastric bypass. Obesity 2013; 21:951-956.
98. Chan JL, Wong SL, Mantzoros CS. Pharmacokinetics of subcutaneous recombinant methionyl human leptin administration in healthy subjects in the fed and fasting states: regulation by gender and adiposity. Clin Pharmacokinet 2008; 47:753-764.
99. Ahren B, Baldwin RM, Havel PJ. Pharmacokinetics of human leptin in mice and rhesus monkeys. Int J Obes Relat Metab Disord 2000; 24:1579-1585.
100. Morath V, Bolze F, Schlapschy M, et al. PASylation of murine leptin leads to extended plasma half-life and enhanced in vivo efficacy. Mol Pharm 2015; 12:1431-1442.
101. Yi X, Yuan D, Farr SA, et al. Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity. J Controlled Release 2014; 191:34-46.
102. Tam CS, Lecoultre V, Ravussin E. Novel strategy for the use of leptin for obesity therapy. Expert Opin Biol Ther 2011; 11:1677-1685.
103. Yan C, Yang Y, Saito K, et al. Meta-Chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice. Br J Pharmacol 2015; 172:3510-3521.
104. DoddGT, Decherf S, Loh K, et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 2015; 160:88-104.
105. Kanoski SE, Ong ZY, Fortin SM, et al. Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms. Diabetes Obes Metab 2015; 17:285-293.