Navegar

Colección

Datos Estadísticas

Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Objective A major challenge for obesity treatment is the maintenance of reduced body weight. Diet-induced obese mice are resistant to achieving normoweight once the obesogenic conditions are reversed, in part because lowered circulating leptin leads to a reduction in metabolic rate and a rebound of hyperphagia that defend the previously elevated body weight set point. Because hypothalamic POMC is a central leptin target, we investigated whether changes in circulating leptin modify Pomc expression to maintain normal energy balance in genetically predisposed obese mice. Methods Mice with reversible Pomc silencing in the arcuate nucleus (ArcPomc−/−) become morbidly obese eating low-fat chow. We measured body composition, food intake, plasma leptin, and leptin sensitivity in ArcPomc−/− mice weight-matched to littermate controls by calorie restriction, either from weaning or after developing obesity. Pomc was reactivated by tamoxifen-dependent Cre recombinase transgenes. Long acting PASylated leptin was administered to weight-reduced ArcPomc−/− mice to mimic the super-elevated leptin levels of obese mice. Results ArcPomc−/− mice had increased adiposity and leptin levels shortly after weaning. Despite chronic calorie restriction to achieve normoweight, ArcPomc−/− mice remained moderately hyperleptinemic and resistant to exogenous leptin's effects to reduce weight and food intake. However, subsequent Pomc reactivation in weight-matched ArcPomc−/− mice normalized plasma leptin, leptin sensitivity, adiposity, and food intake. In contrast, extreme hyperleptinemia induced by PASylated leptin blocked the full restoration of hypothalamic Pomc expression in calorie restricted ArcPomc−/− mice, which consequently regained 30% of their lost body weight and attained a metabolic steady state similar to that of tamoxifen treated obese ArcPomc−/− mice. Conclusions Pomc reactivation in previously obese, calorie-restricted ArcPomc−/− mice normalized energy homeostasis, suggesting that their body weight set point was restored to control levels. In contrast, massively obese and hyperleptinemic ArcPomc−/− mice or those weight-matched and treated with PASylated leptin to maintain extreme hyperleptinemia prior to Pomc reactivation converged to an intermediate set point relative to lean control and obese ArcPomc−/− mice. We conclude that restoration of hypothalamic leptin sensitivity and Pomc expression is necessary for obese ArcPomc−/− mice to achieve and sustain normal metabolic homeostasis; whereas deficits in either parameter set a maladaptive allostatic balance that defends increased adiposity and body weight. © 2016 The Author(s)

Registro:

Documento: Artículo
Título:Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity
Autor:Chhabra, K.H.; Adams, J.M.; Jones, G.L.; Yamashita, M.; Schlapschy, M.; Skerra, A.; Rubinstein, M.; Low, M.J.
Filiación:Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, United States
Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, Freising (Weihenstephan), 85354, Germany
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, 1428, Argentina
Palabras clave:Body weight set point; Hypothalamus; Leptin; Leptin resistance; Obesity; PASylation; POMC; cre recombinase; leptin; proopiomelanocortin; tamoxifen; animal experiment; animal model; animal tissue; anthropometric parameters; arcuate nucleus; Article; body composition; body weight set point; caloric restriction; controlled study; energy balance; female; food intake; gene activation; gene expression; genetic predisposition; hormone blood level; hormone sensitivity; hyperleptinemia; hypothalamus; low fat diet; male; metabolic balance; metabolic stability; morbid obesity; mouse; nonhuman; Pomc gene; priority journal; steady state; transgene; weight gain; weight reduction
Año:2016
Volumen:5
Número:10
Página de inicio:869
Página de fin:881
DOI: http://dx.doi.org/10.1016/j.molmet.2016.07.012
Título revista:Molecular Metabolism
Título revista abreviado:Mol. Metab.
ISSN:22128778
CAS:proopiomelanocortin, 66796-54-1; tamoxifen, 10540-29-1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_22128778_v5_n10_p869_Chhabra

Referencias:

  • Wadden, T.A., Treatment of obesity by moderate and severe caloric restriction: results of clinical research trials (1993) Annals of Internal Medicine, 119 (7_Part_2), pp. 688-693
  • Rosenbaum, M., Leibel, R.L., 20 years of leptin: role of leptin in energy homeostasis in humans (2014) Journal of Endocrinology, 223 (1), pp. T83-T96
  • Elliot, D.L., Goldberg, L., Kuehl, K.S., Bennett, W.M., Sustained depression of the resting metabolic rate after massive weight loss (1989) The American Journal of Clinical Nutrition, 49 (1), pp. 93-96
  • Martin, C.K., Heilbronn, L.K., de Jonge, L., DeLany, J.P., Volaufova, J., Anton, S.D., Effect of calorie restriction on resting metabolic rate and spontaneous physical activity (2007) Obesity (Silver Spring), 15 (12), pp. 2964-2973
  • Byrne, N.M., Wood, R.E., Schutz, Y., Hills, A.P., Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention? (2012) International Journal of Obesity (London), 36 (11), pp. 1472-1478
  • Kissileff, H.R., Thornton, J.C., Torres, M.I., Pavlovich, K., Mayer, L.S., Kalari, V., Leptin reverses declines in satiation in weight-reduced obese humans (2012) The American Journal of Clinical Nutrition, 95 (2), pp. 309-317
  • Knuth, N.D., Johannsen, D.L., Tamboli, R.A., Marks-Shulman, P.A., Huizenga, R., Chen, K.Y., Metabolic adaptation following massive weight loss is related to the degree of energy imbalance and changes in circulating leptin (2014) Obesity (Silver Spring), 22 (12), pp. 2563-2569
  • Fothergill, E., Guo, J., Howard, L., Kerns, J.C., Knuth, N.D., Brychta, R., Persistent metabolic adaptation 6 years after “The Biggest Loser” competition (2016) Obesity (Silver Spring), 24 (8), pp. 1612-1619
  • Weinsier, R.L., Nagy, T.R., Hunter, G.R., Darnell, B.E., Hensrud, D.D., Weiss, H.L., Do adaptive changes in metabolic rate favor weight regain in weight-reduced individuals? An examination of the set-point theory (2000) The American Journal of Clinical Nutrition, 72 (5), pp. 1088-1094
  • Quarta, C., Sanchez-Garrido, M.A., Tschop, M.H., Clemmensen, C., Renaissance of leptin for obesity therapy (2016) Diabetologia, 59 (5), pp. 920-927
  • Guo, J., Jou, W., Gavrilova, O., Hall, K.D., Persistent diet-induced obesity in male C57BL/6 mice resulting from temporary obesigenic diets (2009) PLoS One, 4 (4), p. e5370
  • Ravussin, Y., Gutman, R., Diano, S., Shanabrough, M., Borok, E., Sarman, B., Effects of chronic weight perturbation on energy homeostasis and brain structure in mice (2011) American Journal of Physiology – Regulatory, Integrative and Comparative Physiology, 300 (6), pp. R1352-R1362
  • Schmitz, J., Evers, N., Awazawa, M., Nicholls, H.T., Bronneke, H.S., Dietrich, A., Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss (2016) Molecular Metabolism, 5 (5), pp. 328-339
  • Hao, Z., Mumphrey, M.B., Townsend, R.L., Morrison, C.D., Munzberg, H., Ye, J., Reprogramming of defended body weight after Roux-En-Y gastric bypass surgery in diet-induced obese mice (2016) Obesity (Silver Spring), 24 (3), pp. 654-660
  • Ravussin, Y., LeDuc, C.A., Watanabe, K., Mueller, B.R., Skowronski, A., Rosenbaum, M., Effects of chronic leptin infusion on subsequent body weight and composition in mice: can body weight set point be reset? (2014) Molecular Metabolism, 3 (4), pp. 432-440
  • Thaler, J.P., Guyenet, S.J., Dorfman, M.D., Wisse, B.E., Schwartz, M.W., Hypothalamic inflammation: marker or mechanism of obesity pathogenesis? (2013) Diabetes, 62 (8), pp. 2629-2634
  • Bumaschny, V.F., Yamashita, M., Casas-Cordero, R., Otero-Corchon, V., de Souza, F.S., Rubinstein, M., Obesity-programmed mice are rescued by early genetic intervention (2012) The Journal of Clinical Investigation, 122 (11), pp. 4203-4212
  • Lam, D.D., de Souza, F.S., Nasif, S., Yamashita, M., Lopez-Leal, R., Otero-Corchon, V., Partially redundant enhancers cooperatively maintain Mammalian pomc expression above a critical functional threshold (2015) PLoS Genetics, 11 (2), p. e1004935
  • De Jonghe, B.C., Hayes, M.R., Bence, K.K., Melanocortin control of energy balance: evidence from rodent models (2011) Cellular and Molecular Life Sciences, 68 (15), pp. 2569-2588
  • Kask, A., Rago, L., Wikberg, J.E., Schioth, H.B., Evidence for involvement of the melanocortin MC4 receptor in the effects of leptin on food intake and body weight (1998) European Journal of Pharmacology, 360 (1), pp. 15-19
  • Zhang, Y., Kilroy, G.E., Henagan, T.M., Prpic-Uhing, V., Richards, W.G., Bannon, A.W., Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin (2005) FASEB Journal, 19 (11), pp. 1482-1491
  • Rahmouni, K., Haynes, W.G., Morgan, D.A., Mark, A.L., Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin (2003) The Journal of Neuroscience, 23 (14), pp. 5998-6004
  • Goncalves, G.H., Li, W., Garcia, A.V., Figueiredo, M.S., Bjorbaek, C., Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions (2014) Cell Reports, 7 (4), pp. 1093-1103
  • Trevaskis, J.L., Butler, A.A., Double leptin and melanocortin-4 receptor gene mutations have an additive effect on fat mass and are associated with reduced effects of leptin on weight loss and food intake (2005) Endocrinology, 146 (10), pp. 4257-4265
  • Ceccarini, G., Maffei, M., Vitti, P., Santini, F., Fuel homeostasis and locomotor behavior: role of leptin and melanocortin pathways (2015) Journal of Endocrinological Investigation, 38 (2), pp. 125-131
  • Halaas, J.L., Gajiwala, K.S., Maffei, M., Cohen, S.L., Chait, B.T., Rabinowitz, D., Weight-reducing effects of the plasma protein encoded by the obese gene (1995) Science, 269 (5223), pp. 543-546
  • Heymsfield, S.B., Greenberg, A.S., Fujioka, K., Dixon, R.M., Kushner, R., Hunt, T., Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial (1999) JAMA, 282 (16), pp. 1568-1575
  • Marsh, D.J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K.A., Fisher, S.L., Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides (1999) Nature Genetics, 21 (1), pp. 119-122
  • Ottaway, N., Mahbod, P., Rivero, B., Norman, L.A., Gertler, A., D'Alessio, D.A., Diet-induced obese mice retain endogenous leptin action (2015) Cell Metabolism, 21 (6), pp. 877-882
  • Seeley, R.J., Yagaloff, K.A., Fisher, S.L., Burn, P., Thiele, T.E., van Dijk, G., Melanocortin receptors in leptin effects (1997) Nature, 390 (6658), p. 349
  • Mizuno, T.M., Kleopoulos, S.P., Bergen, H.T., Roberts, J.L., Priest, C.A., Mobbs, C.V., Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin (1998) Diabetes, 47 (2), pp. 294-297
  • Lam, D.D., Attard, C.A., Mercer, A.J., Myers, M.G., Jr., Rubinstein, M., Low, M.J., Conditional expression of Pomc in the Lepr-positive subpopulation of POMC neurons is sufficient for normal energy homeostasis and metabolism (2015) Endocrinology, 156 (4), pp. 1292-1302
  • Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdan, M.G., Diano, S., Horvath, T.L., Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus (2001) Nature, 411 (6836), pp. 480-484
  • Morath, V., Bolze, F., Schlapschy, M., Schneider, S., Sedlmayer, F., Seyfarth, K., PASylation of murine leptin leads to extended plasma half-life and enhanced in vivo efficacy (2015) Molecular Pharmaceutics, 12 (5), pp. 1431-1442
  • Bolze, F., Morath, V., Bast, A., Rink, N., Schlapschy, M., Mocek, S., Long-acting PASylated leptin ameliorates obesity by promoting satiety and preventing hypometabolism in leptin-deficient Lep(ob/ob) mice (2016) Endocrinology, 157 (1), pp. 233-244
  • Berglund, E.D., Liu, C., Sohn, J.W., Liu, T., Kim, M.H., Lee, C.E., Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis (2013) The Journal of Clinical Investigation, 123 (12), pp. 5061-5070
  • Chhabra, K.H., Adams, J.M., Fagel, B., Lam, D.D., Qi, N., Rubinstein, M., Hypothalamic POMC-deficiency improves glucose tolerance despite insulin resistance by increasing glycosuria (2016) Diabetes, 65 (3), pp. 660-672
  • Mercer, A.J., Stuart, R.C., Attard, C.A., Otero-Corchon, V., Nillni, E.A., Low, M.J., Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice (2014) American Journal of Physiology. Endocrinology and Metabolism, 306 (8), pp. E904-E915
  • Banks, W.A., DiPalma, C.R., Farrell, C.L., Impaired transport of leptin across the blood-brain barrier in obesity (1999) Peptides, 20 (11), pp. 1341-1345
  • Banks, W.A., Coon, A.B., Robinson, S.M., Moinuddin, A., Shultz, J.M., Nakaoke, R., Triglycerides induce leptin resistance at the blood–brain barrier (2004) Diabetes, 53 (5), pp. 1253-1260
  • Banks, W.A., Farrell, C.L., Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible (2003) American Journal of Physiology. Endocrinology and Metabolism, 285 (1), pp. E10-E15
  • Tolle, V., Low, M.J., In vivo evidence for inverse agonism of Agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice (2008) Diabetes, 57 (1), pp. 86-94
  • Enriori, P.J., Evans, A.E., Sinnayah, P., Jobst, E.E., Tonelli-Lemos, L., Billes, S.K., Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons (2007) Cell Metabolism, 5 (3), pp. 181-194
  • Munzberg, H., Flier, J.S., Bjorbaek, C., Region-specific leptin resistance within the hypothalamus of diet-induced obese mice (2004) Endocrinology, 145 (11), pp. 4880-4889
  • Frederich, R.C., Hamann, A., Anderson, S., Lollmann, B., Lowell, B.B., Flier, J.S., Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action (1995) Nature Medicine, 1 (12), pp. 1311-1314
  • Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Targeted disruption of the melanocortin-4 receptor results in obesity in mice (1997) Cell, 88 (1), pp. 131-141
  • Overstreet, L.S., Hentges, S.T., Bumaschny, V.F., de Souza, F.S., Smart, J.L., Santangelo, A.M., A transgenic marker for newly born granule cells in dentate gyrus (2004) The Journal of Neuroscience, 24 (13), pp. 3251-3259
  • Appleyard, S.M., Bailey, T.W., Doyle, M.W., Jin, Y.H., Smart, J.L., Low, M.J., Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids (2005) The Journal of Neuroscience, 25 (14), pp. 3578-3585
  • Niikura, K., Zhou, Y., Ho, A., Kreek, M.J., Proopiomelanocortin (POMC) expression and conditioned place aversion during protracted withdrawal from chronic intermittent escalating-dose heroin in POMC-EGFP promoter transgenic mice (2013) Neuroscience, 236, pp. 220-232
  • Page-Wilson, G., Meece, K., White, A., Rosenbaum, M., Leibel, R.L., Smiley, R., Proopiomelanocortin, agouti-related protein, and leptin in human cerebrospinal fluid: correlations with body weight and adiposity (2015) American Journal of Physiology. Endocrinology and Metabolism, 309 (5), pp. E458-E465
  • Zelissen, P.M.J., Stenlof, K., Lean, M.E.J., Fogteloo, J., Keulen, E.T.P., Wilding, J., Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial (2005) Diabetes, Obesity and Metabolism, 7 (6), pp. 755-761
  • Benoit, S.C., Schwartz, M.W., Lachey, J.L., Hagan, M.M., Rushing, P.A., Blake, K.A., A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences (2000) The Journal of Neuroscience, 20 (9), pp. 3442-3448
  • Burke, L.K., Doslikova, B., D'Agostino, G., Greenwald-Yarnell, M., Georgescu, T., Chianese, R., Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons (2016) Molecular Metabolism, 5 (3), pp. 245-252
  • Knight, Z.A., Hannan, K.S., Greenberg, M.L., Friedman, J.M., Hyperleptinemia is required for the development of leptin resistance (2010) PLoS One, 5 (6), p. e11376
  • Gamber, K.M., Huo, L., Ha, S., Hairston, J.E., Greeley, S., Bjorbaek, C., Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity (2012) PLoS One, 7 (1), p. e30485
  • Renquist, B.J., Murphy, J.G., Larson, E.A., Olsen, D., Klein, R.F., Ellacott, K.L.J., Melanocortin-3 receptor regulates the normal fasting response (2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (23), pp. E1489-E1498
  • Chen, A.S., Marsh, D.J., Trumbauer, M.E., Frazier, E.G., Guan, X.M., Yu, H., Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass (2000) Nature Genetics, 26 (1), pp. 97-102
  • Nogueiras, R., Wiedmer, P., Perez-Tilve, D., Veyrat-Durebex, C., Keogh, J.M., Sutton, G.M., The central melanocortin system directly controls peripheral lipid metabolism (2007) Journal of Clinical Investigation, 117 (11), pp. 3475-3488

Citas:

---------- APA ----------
Chhabra, K.H., Adams, J.M., Jones, G.L., Yamashita, M., Schlapschy, M., Skerra, A., Rubinstein, M.,..., Low, M.J. (2016) . Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity. Molecular Metabolism, 5(10), 869-881.
http://dx.doi.org/10.1016/j.molmet.2016.07.012
---------- CHICAGO ----------
Chhabra, K.H., Adams, J.M., Jones, G.L., Yamashita, M., Schlapschy, M., Skerra, A., et al. "Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity" . Molecular Metabolism 5, no. 10 (2016) : 869-881.
http://dx.doi.org/10.1016/j.molmet.2016.07.012
---------- MLA ----------
Chhabra, K.H., Adams, J.M., Jones, G.L., Yamashita, M., Schlapschy, M., Skerra, A., et al. "Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity" . Molecular Metabolism, vol. 5, no. 10, 2016, pp. 869-881.
http://dx.doi.org/10.1016/j.molmet.2016.07.012
---------- VANCOUVER ----------
Chhabra, K.H., Adams, J.M., Jones, G.L., Yamashita, M., Schlapschy, M., Skerra, A., et al. Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity. Mol. Metab. 2016;5(10):869-881.
http://dx.doi.org/10.1016/j.molmet.2016.07.012