ometendoОжирение и метаболизмObesity and metabolism2071-87132306-5524Endocrinology Research Centre10.14341/2071-8713-5202ometendo-5202Research ArticleСтатьиArticlesЛептин и его медиаторы в регуляциижирового обменаLeptin i ego mediatory v regulyatsiizhirovogo obmenaPankovYu Ayupank10@gmail.com20101506201072№2 (2010)39Copyright © Pankov Y.A., 20102010Pankov Y.A.Pankov Y.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.omet-endojournals.ru/jour/article/view/5202

Резюме. Мутации в генах LEP, LEPR, POMC и MC4R индуцируют ожирение и нарушение других физиологических функций. Блокада экспрессии LEP и LEPR сочетается у гомозигот с тяжелым ожирением, задержкой полового развития, инсулинорезистентностью, снижением секреции гормонов гипофиза и иммунодефицитом. Мутации в POMC в гомозиготном состоянии ассоциируются у человека с морбидным ожирением и острой недостаточностью коры надпочечников. В гетерозиготном со стоянии мутации в POMC предрасполагают к ожирению, но не влияют на другие функции. Мутации в MC4R - наиболее частая причина ожирения. Они ассоциируются с суровым нарушением жирового обмена у гомозигот, но более легкой патологией у гетерозигот. Ожирение, вызванное мутациями в MC4R, обычно не сопровождается изменениями других физиологических функций. Resume. Mutations in LEP, LEPR, PNC and MC4R genes induce obesity and deterioration of other physiological functions. Blockage of LEP and LEPR expression in homozygotes leads to severe obesity, delay in sexual development, insulin resistance, decreased secretion of pituitary hormones and immunodeficiency. Mutations of POMC in homozygote variant are associated in humans with morbid obesity and acute adrenocortical deficiency. In heterozygotes mutations of POMC predispose to obesity, but have no influence on other functions. Mutations in MC4R gene are the most common cause of obesity. They are associated with severe deterioration of lipid metabolism in homozygotes, but with more mild pathology in heterozygotes. Obesity from the mutation in MC4R gene usually is not accompanied by changes in other physiologic function.

генмутациягормонрецепторожирениеgenemutationhormonereceptorobesityReferencesОgden C.L., Carroll M.D., Curtin L.D. et al. Prevalence of overweight and obesity in the United States, 1999-2004 // JAMA 2006; 295: 1549-1555.Оgden C.L., Carroll M.D., Curtin L.D. et al. Prevalence of overweight and obesity in the United States, 1999-2004 // JAMA 2006; 295: 1549-1555.Панков Ю.А. Достижения в исследовании действия лептина на нейроны гипоталамуса // Эволюц. биохим. физиол., 2000; 36: 509-514.Панков Ю.А. Достижения в исследовании действия лептина на нейроны гипоталамуса // Эволюц. биохим. физиол., 2000; 36: 509-514.Панков Ю.А., Чехранова М.К., Карпова С.К. «Переплетение» молекулярных механизмов действия различных гормонов и их роль в патогенезе ожирения, инсу- линорезистентности и сахарного диабета // Вестник РАМН, 2008; 3: 28-36.Панков Ю.А., Чехранова М.К., Карпова С.К. «Переплетение» молекулярных механизмов действия различных гормонов и их роль в патогенезе ожирения, инсу- линорезистентности и сахарного диабета // Вестник РАМН, 2008; 3: 28-36.Панков Ю.А. Лептин - новый гормон в эндокринологии // Успехи физиологических наук, 2003; 34: 3-20.Панков Ю.А. Лептин - новый гормон в эндокринологии // Успехи физиологических наук, 2003; 34: 3-20.Clement K., Vaisse C., Lahlou N. et al. A mutation in the human leptin gene causes obesity and pituitary dysfunction // Nature, 1998; 392: 398-401.Clement K., Vaisse C., Lahlou N. et al. A mutation in the human leptin gene causes obesity and pituitary dysfunction // Nature, 1998; 392: 398-401.Kimber W., Peelman F., Prieur X. et al. Functional characterization of naturally occurring pathogenic mutations in the human leptin gene // Endocrinology, 2008; 149: 6043-6052.Kimber W., Peelman F., Prieur X. et al. Functional characterization of naturally occurring pathogenic mutations in the human leptin gene // Endocrinology, 2008; 149: 6043-6052.Farooqi I.S., Wangensteen T., Collins S. et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor // New. Engl. J. Med., 2007; 356: 237-247.Farooqi I.S., Wangensteen T., Collins S. et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor // New. Engl. J. Med., 2007; 356: 237-247.Duarte F.F., Fracischetti E.A., Genelhu-Abreu V. et al. p.Q223R leptin receptor polymorphism associated with obesity in Brazilian multiethnic subjects // Am. J. Hum. Biol., 2006; 18: 448-453.Duarte F.F., Fracischetti E.A., Genelhu-Abreu V. et al. p.Q223R leptin receptor polymorphism associated with obesity in Brazilian multiethnic subjects // Am. J. Hum. Biol., 2006; 18: 448-453.Montague C.T., Farooqi I.S., Whitehead J.P. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans // Nature, 1997; 387: 903-908.Montague C.T., Farooqi I.S., Whitehead J.P. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans // Nature, 1997; 387: 903-908.Farooqi I.S., Matarese G., Lord G.M. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiviness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency // J. Clin. Invest., 2002; 110: 1093-1103.Farooqi I.S., Matarese G., Lord G.M. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiviness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency // J. Clin. Invest., 2002; 110: 1093-1103.Strobel A., Issad T., Camoin l. et al. A leptin missense muration associated with hypogonadism and morbid obesity // Nat. Genet., 1998; 18: 213-215.Strobel A., Issad T., Camoin l. et al. A leptin missense muration associated with hypogonadism and morbid obesity // Nat. Genet., 1998; 18: 213-215.Ozata M., Ozdemir 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 leptinmediated defects // J. Clin. Endocrinol. Metab., 1999; 84: 3686-3695.Ozata M., Ozdemir 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 leptinmediated defects // J. Clin. Endocrinol. Metab., 1999; 84: 3686-3695.Licinio J., Caglayan S., Ozata M. et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults // PNAS 2004; 101: 4531-4536.Licinio J., Caglayan S., Ozata M. et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults // PNAS 2004; 101: 4531-4536.Paz-Filho C., Delibasi T., Erol H.K. et al. Congenital leptin deficiency and thyroid function // Thyroid Research 2009; 2: 11-14.Paz-Filho C., Delibasi T., Erol H.K. et al. Congenital leptin deficiency and thyroid function // Thyroid Research 2009; 2: 11-14.Pelleymounter M.A., Cullen M.G., Baker M. et al. Effects of the obese gene product on body weight regulation in ob/ob mice // Science, 1995; 269: 540-543.Pelleymounter M.A., Cullen M.G., Baker M. et al. Effects of the obese gene product on body weight regulation in ob/ob mice // Science, 1995; 269: 540-543.Chekhranova M.K., Karpova S.K., Yatsyshina S.B. et al. A new mutation c. 422C>G(p.S141C) in homo- and heterozygous forms of the human leptin gene // Russian J. Bioorganic. Chem., 2008; 34: 768-770.Chekhranova M.K., Karpova S.K., Yatsyshina S.B. et al. A new mutation c. 422C>G(p.S141C) in homo- and heterozygous forms of the human leptin gene // Russian J. Bioorganic. Chem., 2008; 34: 768-770.Zhang Y., Proenca R., Maffei M. et al. Positional cloning of mouse obese gene and its human homolog // Nature, 1994; 372: 425-431.Zhang Y., Proenca R., Maffei M. et al. Positional cloning of mouse obese gene and its human homolog // Nature, 1994; 372: 425-431.Krude H., Bieberman H., Schnabel D. et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10 // J. Clin. Endocrinol. Metab., 2003; 88: 4633-4640.Krude H., Bieberman H., Schnabel D. et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10 // J. Clin. Endocrinol. Metab., 2003; 88: 4633-4640.Farooqi I.S., Drop S., Clements A. et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans // Diabetes, 2006; 55: 2549-2553.Farooqi I.S., Drop S., Clements A. et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans // Diabetes, 2006; 55: 2549-2553.Clement K., Dubern B., Mencarelli M. et al. Unexpected endocrine features and normal pigmentation in young adult patient carrying a novel homozygous mutation in the POMC gene // J. Clin. Endocrinol. Metab., 2008; 93: 4955-4962.Clement K., Dubern B., Mencarelli M. et al. Unexpected endocrine features and normal pigmentation in young adult patient carrying a novel homozygous mutation in the POMC gene // J. Clin. Endocrinol. Metab., 2008; 93: 4955-4962.Hinney A., Becker O., Heibult O. et al. Systematic mutation screening of the proopiomelanocortin gene: identification of several genetic variants including three different insertions, one nonsense and two missense point mutations in probands of different weight extremes // J. Clin. Endocrinol. Metabl., 2002; 83: 3737-3741.Hinney A., Becker O., Heibult O. et al. Systematic mutation screening of the proopiomelanocortin gene: identification of several genetic variants including three different insertions, one nonsense and two missense point mutations in probands of different weight extremes // J. Clin. Endocrinol. Metabl., 2002; 83: 3737-3741.Панков Ю.А., Яцышина С.Б., Карпова С.К. и др. Скрининг мутаций в гене про- опиомеланокортина у больных конституционным ожирением // Вопр. мед. химии, 2002; 48: 120-131.Панков Ю.А., Яцышина С.Б., Карпова С.К. и др. Скрининг мутаций в гене про- опиомеланокортина у больных конституционным ожирением // Вопр. мед. химии, 2002; 48: 120-131.Панков Ю.А., Чехранова М.К., Карпова С.К. и др. Скрининг мутаций в генах проопиомеланокортина и рецептора 4 меланокортинов, ассоциированных с ожирением // Мед. генетика., 2006; 46(4б): 27-33.Панков Ю.А., Чехранова М.К., Карпова С.К. и др. Скрининг мутаций в генах проопиомеланокортина и рецептора 4 меланокортинов, ассоциированных с ожирением // Мед. генетика., 2006; 46(4б): 27-33.Lee Y.S., Challis B.G., Thompson D.A. et al. A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance // Cell. Metab., 2006; 3: 135-140.Lee Y.S., Challis B.G., Thompson D.A. et al. A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance // Cell. Metab., 2006; 3: 135-140.Biebermann H., Castaneda T.R., van Landeghem F. et al. A role for β-melanocytestimulating hormone in human body-weight regulation // Cell. Metab., 2006; 3: 141-146.Biebermann H., Castaneda T.R., van Landeghem F. et al. A role for β-melanocytestimulating hormone in human body-weight regulation // Cell. Metab., 2006; 3: 141-146.Dubern B., Lubrano-Berthelier C., Mencarelli M. et al. Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of the novel deleterious heterozygous mutation located in the α-melanocyte stimulating hormone domain // Pediatric. Research., 2008; 63: 211-216.Dubern B., Lubrano-Berthelier C., Mencarelli M. et al. Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of the novel deleterious heterozygous mutation located in the α-melanocyte stimulating hormone domain // Pediatric. Research., 2008; 63: 211-216.Pritchard L.E., White A. Minireview: Neuropeptide processing and its impact on melanocortin pathways // Endocrinology, 2007; 148: 4201-4207.Pritchard L.E., White A. Minireview: Neuropeptide processing and its impact on melanocortin pathways // Endocrinology, 2007; 148: 4201-4207.Сreemers J.W.M., Lee Y.S., Oliver R.L. et al. Mutations in the amino-terminal region of proopiomelanocortin (POMC) in patients with early-onset obesity impair POMC sorting to the regulated secretory pathway // J. Clin. Endocrinol. Metab., 2008; 93: 4494-4499.Сreemers J.W.M., Lee Y.S., Oliver R.L. et al. Mutations in the amino-terminal region of proopiomelanocortin (POMC) in patients with early-onset obesity impair POMC sorting to the regulated secretory pathway // J. Clin. Endocrinol. Metab., 2008; 93: 4494-4499.Zhang K., Kaufman R. From endoplasmic-reticulum stress to the inflommatory response // Nature 2008; 454: 455-462.Zhang K., Kaufman R. From endoplasmic-reticulum stress to the inflommatory response // Nature 2008; 454: 455-462.Eizirik D.L., Cardozo A.K., Cnop M. The role of endoplasmic reticulum stress in diabetes mellitus // Endocrine Rev., 2008; 29: 42-61.Eizirik D.L., Cardozo A.K., Cnop M. The role of endoplasmic reticulum stress in diabetes mellitus // Endocrine Rev., 2008; 29: 42-61.Yeo G.S.H., Farooqi I.S., Aminian S. et al. A frameshift mutation in human MC4R is associated dominantly inherited human obesity // Nat. Genet., 1998; 20: 111- 112.Yeo G.S.H., Farooqi I.S., Aminian S. et al. A frameshift mutation in human MC4R is associated dominantly inherited human obesity // Nat. Genet., 1998; 20: 111- 112.Vaisse C., Clement K., Guy-Grand B. A frameshift mutation in human MC4R is associated with dominant form of obesity // Nat. Genet., 1998; 20: 113-114.Vaisse C., Clement K., Guy-Grand B. A frameshift mutation in human MC4R is associated with dominant form of obesity // Nat. Genet., 1998; 20: 113-114.Lubrano-Berthelier C., Le Stunff C., Bougneres P. et al. A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans // J. Clin. Endocrinol. Metab., 2004; 89: 2028-2032.Lubrano-Berthelier C., Le Stunff C., Bougneres P. et al. A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans // J. Clin. Endocrinol. Metab., 2004; 89: 2028-2032.Farooqi I.S., Keogh J.M., Yeo G.S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene // N. Engl. J. Med., 2003; 348: 1085-1095.Farooqi I.S., Keogh J.M., Yeo G.S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene // N. Engl. J. Med., 2003; 348: 1085-1095.Lubrano-Berhelier C., Dubern B., Lacorte J.M. et al. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating // J. Clin. Endocrinol. Metab., 2006; 91: 1811-1818.Lubrano-Berhelier C., Dubern B., Lacorte J.M. et al. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating // J. Clin. Endocrinol. Metab., 2006; 91: 1811-1818.Lubrano-Berthelier C., Durand E., Dubern B. et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations // Hum. Mol. Genet., 2003; 12: 145-153.Lubrano-Berthelier C., Durand E., Dubern B. et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations // Hum. Mol. Genet., 2003; 12: 145-153.Srinivasan S., Lubrano-Berthelier C., Govaerts C. et al. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans // J. Clin. Invest., 2004; 114: 1158-1164.Srinivasan S., Lubrano-Berthelier C., Govaerts C. et al. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans // J. Clin. Invest., 2004; 114: 1158-1164.Pankov Y.A. Adipose tissue as an endocrine organ regulating growth, puberty, and other physiological functions // Biochemistry (Moscow) 1999; 64: 601-609.Pankov Y.A. Adipose tissue as an endocrine organ regulating growth, puberty, and other physiological functions // Biochemistry (Moscow) 1999; 64: 601-609.Loos R.J., Lindgren C.M., Li S. et al. Common variants near MC4R is associated with fat mass, weight and risk of obesity // Nat. Genet., 2008; 40: 768-775.Loos R.J., Lindgren C.M., Li S. et al. Common variants near MC4R is associated with fat mass, weight and risk of obesity // Nat. Genet., 2008; 40: 768-775.Thorlefssen G., Walters G.B., Gudbjartsson D.F. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity // Nat. Genet., 2009; 41: 18-24.Thorlefssen G., Walters G.B., Gudbjartsson D.F. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity // Nat. Genet., 2009; 41: 18-24.Willer C.J., Speliotes E.K., Loos R.J.F. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation // Nat. Genet., 2009; 41: 25-34.Willer C.J., Speliotes E.K., Loos R.J.F. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation // Nat. Genet., 2009; 41: 25-34.Wardle J., Carnel S., Haworth C.M.A. et al. Obesity associated genetic variation in FTO is associated with diminished satiety // J. Clin. Endocrinol. Metab., 2008; 93: 3640-3643.Wardle J., Carnel S., Haworth C.M.A. et al. Obesity associated genetic variation in FTO is associated with diminished satiety // J. Clin. Endocrinol. Metab., 2008; 93: 3640-3643.Meyer D., Delplanque J., Chevre J-C. et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European population // Nat. Genet., 2009; 41: 157-159.Meyer D., Delplanque J., Chevre J-C. et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European population // Nat. Genet., 2009; 41: 157-159.

The authors declare that there are no conflicts of interest present.