Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase

Pablo B Martínez de Morentin, Andrew J Whittle, Johan Fernø, Rubén Nogueiras, Carlos Diéguez, Antonio Vidal-Puig, Miguel López, Pablo B Martínez de Morentin, Andrew J Whittle, Johan Fernø, Rubén Nogueiras, Carlos Diéguez, Antonio Vidal-Puig, Miguel López

Abstract

Smokers around the world commonly report increased body weight after smoking cessation as a major factor that interferes with their attempts to quit. Numerous controlled studies in both humans and rodents have reported that nicotine exerts a marked anorectic action. The effects of nicotine on energy homeostasis have been mostly pinpointed in the central nervous system, but the molecular mechanisms controlling its action are still not fully understood. The aim of this study was to investigate the effect of nicotine on hypothalamic AMP-activated protein kinase (AMPK) and its effect on energy balance. Here we demonstrate that nicotine-induced weight loss is associated with inactivation of hypothalamic AMPK, decreased orexigenic signaling in the hypothalamus, increased energy expenditure as a result of increased locomotor activity, increased thermogenesis in brown adipose tissue (BAT), and alterations in fuel substrate utilization. Conversely, nicotine withdrawal or genetic activation of hypothalamic AMPK in the ventromedial nucleus of the hypothalamus reversed nicotine-induced negative energy balance. Overall these data demonstrate that the effects of nicotine on energy balance involve specific modulation of the hypothalamic AMPK-BAT axis. These targets may be relevant for the development of new therapies for human obesity.

Figures

FIG. 1.
FIG. 1.
Effects of nicotine administration on energy balance. A: Body weight change. B: Food intake. C: RD. D: CTA. E: Body temperature change. F: EE (cumulative in left panel and total in right panel). G: LA (cumulative in left panel and total in right panel). H: RQ (cumulative in left panel and total in right panel) of vehicle (Veh) and nicotine-treated (Nic) rats for 48 h are shown. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle; ###P < 0.001 nicotine vs. LiCl. In the right panels of F and G, the asterisks above the lines refer to the daily (diurnal + nocturnal) EE or LA. All data are expressed as mean ± SEM.
FIG. 2.
FIG. 2.
Effects of nicotine administration on hypothalamic neuropeptides, AMPK, and BAT thermogenic program. In situ hybridization autoradiographic images (A) and AgRP, NPY, POMC, and CART mRNA levels in the ARC (B), FAS mRNA levels in the VMH (C), hypothalamic FAS activity (D), Western blot autoradiographic images (left panel) and hypothalamic protein levels of the different proteins of the AMPK pathway (right panel) (E), and infrared thermal images (left panel) with quantification of temperature (Temp; right panel) (F) and thermogenic markers (G) in the BAT of vehicle (Veh) and nicotine-treated (Nic) rats for 48 h are shown. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle. 3V, third ventricle. PGC1, peroxisome proliferator–activated receptor γ coactivator 1. All data are expressed as mean ± SEM. (A high-quality digital representation of this figure is available in the online issue.)
FIG. 3.
FIG. 3.
Effect of antagonism of α3β4-nicotinic acetylcholine receptors on nicotine-induced inhibition of hypothalamic AMPK. Body weight change (A), food intake (B), and Western blot autoradiographic images (left panel) and hypothalamic protein levels of the different proteins of the AMPK pathway (right panel) (C) of rats treated with vehicle (Veh), nicotine (Nic), and mecamylamine (Mec). Dividing lines show spliced bands. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle; #P < 0.05, ###P < 0.001 nicotine vehicle vs. nicotine mecamylamine. All data are expressed as mean ± SEM.
FIG. 4.
FIG. 4.
Effects of nicotine withdrawal on energy balance. Body weight (BW) change (A), food intake (B), fat and lean mass (C), EE (D; cumulative in left panel and total in right panel), LA (E; cumulative in left panel and total in right panel), and RQ (F; cumulative in left panel and total in right panel) of vehicle (Veh), nicotine (Nic), and nicotine withdrawal (With) rats are shown. EE, LA, and RQ data are from nicotine and nicotine withdrawal rats during the last 72 h of nicotine cessation. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle; #P < 0.05, ##P < 0.01, ###P < 0.001 nicotine vs. withdrawal; in the right panels of D and E, the symbols above the lines refer to the daily (diurnal + nocturnal) EE or LA. All data are expressed as mean ± SEM.
FIG. 5.
FIG. 5.
Effects of nicotine withdrawal hypothalamic AMPK pathway and BAT thermogenic program. Western blot autoradiographic images (left panel) and hypothalamic protein levels of the different proteins of the AMPK pathway (right panel) (A) and thermogenic markers (B) in the BAT of vehicle, nicotine, and nicotine withdrawal rats. Dividing lines show spliced bands. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle; ##P < 0.01, ###P < 0.001 nicotine vs. withdrawal. HPRT, hypoxanthine-guanine phosphoribosyltransferase; PGC1, peroxisome proliferator–activated receptor γ coactivator 1. All data are expressed as mean ± SEM.
FIG. 6.
FIG. 6.
Effects of hypothalamic AMPK activation on nicotine actions on energy balance, neuropeptides, and BAT thermogenic program. A: Food intake in rats treated with nicotine and the AMPK activator AICAR. Body weight change (B); daily food intake (C); in situ hybridization autoradiographic images (D); AgRP, NPY, and POMC mRNA levels in the ARC (E); and thermogenic markers (F) in the BAT of rats treated with vehicle or nicotine and stereotaxically treated with GFP-expressing adenoviruses or GFP plus AMPK constitutively active (AMPKα-CA) adenoviruses are shown. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle or vehicle GFP; #P < 0.05, ##P < 0.01, ###P < 0.001 nicotine vehicle vs. nicotine AICAR or nicotine GFP vs. nicotine AMPKα-CA. 3V, third ventricle; PGC1, peroxisome proliferator–activated receptor γ coactivator 1; HPRT, hypoxanthine-guanine phosphoribosyltransferase. All data are expressed as mean ± SEM.

References

    1. Filozof C, Fernández Pinilla MC, Fernández-Cruz A. Smoking cessation and weight gain. Obes Rev 2004;5:95–103
    1. Grunberg NE. A neurobiological basis for nicotine withdrawal. Proc Natl Acad Sci USA 2007;104:17901–17902
    1. Mineur YS, Abizaid A, Rao Y, et al. Nicotine decreases food intake through activation of POMC neurons. Science 2011;332:1330–1332
    1. Seeley RJ, Sandoval DA. Neuroscience: weight loss through smoking. Nature 2011;475:176–177
    1. Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 2005;493:63–71
    1. Gao Q, Horvath TL. Neurobiology of feeding and energy expenditure. Annu Rev Neurosci 2007;30:367–398
    1. Xue B, Pulinilkunnil T, Murano I, et al. Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Mol Cell Biol 2009;29:4563–4573
    1. López M, Varela L, Vázquez MJ, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010;16:1001–1008
    1. Lam TK, Pocai A, Gutierrez-Juarez R, et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 2005;11:320–327
    1. Könner AC, Janoschek R, Plum L, et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 2007;5:438–449
    1. Minokoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339–343
    1. Nogueiras R, Wiedmer P, Perez-Tilve D, et al. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 2007;117:3475–3488
    1. Fliers E, Klieverik LP, Kalsbeek A. Novel neural pathways for metabolic effects of thyroid hormone. Trends Endocrinol Metab 2010;21:230–236
    1. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005;1:15–25
    1. Lage R, Diéguez C, Vidal-Puig A, López M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 2008;14:539–549
    1. Minokoshi Y, Alquier T, Furukawa N, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004;428:569–574
    1. Andrews ZB, Liu ZW, Walllingford N, et al. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 2008;454:846–851
    1. López M, Lage R, Saha AK, et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 2008;7:389–399
    1. Jang MH, Shin MC, Kim KH, et al. Nicotine administration decreases neuropeptide Y expression and increases leptin receptor expression in the hypothalamus of food-deprived rats. Brain Res 2003;964:311–315
    1. Bishop C, Parker GC, Coscina DV. Nicotine and its withdrawal alter feeding induced by paraventricular hypothalamic injections of neuropeptide Y in Sprague-Dawley rats. Psychopharmacology (Berl) 2002;162:265–272
    1. Fornari A, Pedrazzi P, Lippi G, Picciotto MR, Zoli M, Zini I. Nicotine withdrawal increases body weight, neuropeptide Y and Agouti-related protein expression in the hypothalamus and decreases uncoupling protein-3 expression in the brown adipose tissue in high-fat fed mice. Neurosci Lett 2007;411:72–76
    1. Hur YN, Hong GH, Choi SH, Shin KH, Chun BG. High fat diet altered the mechanism of energy homeostasis induced by nicotine and withdrawal in C57BL/6 mice. Mol Cells 2010;30:219–226
    1. Arai K, Kim K, Kaneko K, et al. Nicotine infusion alters leptin and uncoupling protein 1 mRNA expression in adipose tissues of rats. Am J Physiol Endocrinol Metab 2001;280:E867–E876
    1. Mano-Otagiri A, Iwasaki-Sekino A, Ohata H, Arai K, Shibasaki T. Nicotine suppresses energy storage through activation of sympathetic outflow to brown adipose tissue via corticotropin-releasing factor type 1 receptor. Neurosci Lett 2009;455:26–29
    1. Li MD, Kane JK, Parker SL, McAllen K, Matta SG, Sharp BM. Nicotine administration enhances NPY expression in the rat hypothalamus. Brain Res 2000;867:157–164
    1. López M, Lelliott CJ, Tovar S, et al. Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 2006;55:1327–1336
    1. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Sydney, Academic Press, 1986
    1. Theander-Carrillo C, Wiedmer P, Cettour-Rose P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 2006;116:1983–1993
    1. Sloan JW, Martin WR, Bostwick M. Mechanisms involved in the respiratory depressant actions of nicotine in anesthetized rats. Pharmacol Biochem Behav 1989;34:559–564
    1. Aberger K, Chitravanshi VC, Sapru HN. Cardiovascular responses to microinjections of nicotine into the caudal ventrolateral medulla of the rat. Brain Res 2001;892:138–146
    1. Dickson SL, Hrabovszky E, Hansson C, et al. Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents. Neuroscience 2010;171:1180–1186
    1. Farooqi IS, O’Rahilly S. Monogenic obesity in humans. Annu Rev Med 2005;56:443–458
    1. Ropelle ER, Flores MB, Cintra DE, et al. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKβ and ER stress inhibition. PLoS Biol 2010;8:e1000465.
    1. Foster-Schubert KE, Cummings DE. Emerging therapeutic strategies for obesity. Endocr Rev 2006;27:779–793
    1. Hampl JS, Betts NM. Cigarette use during adolescence: effects on nutritional status. Nutr Rev 1999;57:215–221
    1. Bize R, Willi C, Chiolero A, et al. Participation in a population-based physical activity programme as an aid for smoking cessation: a randomised trial. Tob Control 2010;19:488–494
    1. Gross J, Stitzer ML, Maldonado J. Nicotine replacement: effects of postcessation weight gain. J Consult Clin Psychol 1989;57:87–92
    1. Yoshida T, Sakane N, Umekawa T, et al. Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice. Int J Obes Relat Metab Disord 1999;23:570–575
    1. Frankish HM, Dryden S, Wang Q, Bing C, MacFarlane IA, Williams G. Nicotine administration reduces neuropeptide Y and neuropeptide Y mRNA concentrations in the rat hypothalamus: NPY may mediate nicotine’s effects on energy balance. Brain Res 1995;694:139–146
    1. Chen H, Hansen MJ, Jones JE, et al. Regulation of hypothalamic NPY by diet and smoking. Peptides 2007;28:384–389
    1. Cannon B, Nedergaard J. Thyroid hormones: igniting brown fat via the brain. Nat Med 2010;16:965–967
    1. Niijima A, Rohner-Jeanrenaud F, Jeanrenaud B. Role of ventromedial hypothalamus on sympathetic efferents of brown adipose tissue. Am J Physiol 1984;247:R650–R654
    1. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004;84:277–359
    1. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444–E452
    1. Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509–1517
    1. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500–1508
    1. Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518–1525
    1. Hofstetter A, Schutz Y, Jéquier E, Wahren J. Increased 24-hour energy expenditure in cigarette smokers. N Engl J Med 1986;314:79–82
    1. Newhouse PA, Potter A, Singh A. Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 2004;4:36–46
    1. Thacker EL, O’Reilly EJ, Weisskopf MG, et al. Temporal relationship between cigarette smoking and risk of Parkinson disease. Neurology 2007;68:764–768

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다