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Central regulation of energy balance: inputs, outputs and leptin resistance

Published online by Cambridge University Press:  07 March 2007

Jonathan R. S. Arch
Jonathan R. S. Arch
Affiliation:
Clore Laboratory, University of Buckingham, Buckingham MK18 1EG, UK
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Abstract

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The regulation of energy balance is complex and, in man, imprecise. Nevertheless, in many individuals intake and expenditure are balanced with <1% error with little or no conscious effect. Essential components of such a regulatory system are signals, leptin and insulin, that reflect the size of lipid stores. Leptin receptors signal via phosphatidylinositol 3-kinase (as do insulin receptors) and via the transcription factor signal transducer and activator of transcription-3 to activate various types of neurone. Obese rodents, and possibly man, are resistant to leptin; in some cases because of genetic or perinatal programming (primary resistance), but commonly in response to high leptin levels (secondary resistance). Secondary leptin resistance may be a result of reduced transport of leptin to the brain or down-regulation of leptin signalling. Signals that reflect lipid stores form the tonic homeostatic regulatory system. They interact with episodic homeostatic signals carried by neurones, hormones and metabolites to regulate meal size and frequency. They also interact with signals related to the palatability of food, biorhythms and learning. Many neurotransmitters and hormones mediate responses to more than one input (e.g. gastric and adipocyte leptin), but are nevertheless most involved with particular inputs (e.g. leptin with adipocyte fat stores). Feeding can be divided into appetitive (preparation for feeding) and consummatory phases, which can both be further subdivided. Different sets of neurotransmitters and hormones are involved at each stage. In the long term it may be possible to customise obesity therapies according to those inputs and outputs that are most disturbed and most amenable to intervention in individual subjects.

Keywords

Energy balance mechanismsLeptin resistanceOrexin
Type
Symposium on ‘Biology of obesity’
Information
Proceedings of the Nutrition Society , Volume 64 , Issue 1 , February 2005 , pp. 39 - 46
Copyright
Copyright © The Nutrition Society 2005

References

Ahima, RS, Kelly, J, Elmquist, JK & Flier, JS (1999) Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia. Endocrinology 140, 4923–4931 CrossRefGoogle ScholarPubMed
Air, EL, Strowski, MZ, Benoit, SC, Conarello, SL, Salituro, GM, Guan, XM, Liu, K, Woods, SC & Zhang, BB (2002) Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity. Nature Medicine 8, 179–183 Google Scholar
Ammar, AA, Sederholm, F, Saito, TR, Scheurink, AJ, Johnson, AE & Sodersten, P (2000) NPY-leptin: opposing effects on appetitive and consummatory ingestive behavior and sexual behavior. American Journal of Physiology 278, R1627–R1633 Google Scholar
Andersson, U, Filipsson, K, Abbott, CR, Woods, A, Smith, K, Bloom, SR, Carling, D & Small, CJ (2004) AMP-activated protein kinase plays a role in the control of food intake. Journal of Biological Chemistry 279, 12005–12008 Google Scholar
Arch, JR (2002) Lessons in obesity from transgenic animals. Journal of Endocrinological Investigation 25, 867–875 Google Scholar
Arch, JRS, Stock, MJ & Trayhurn, P (1998) Leptin resistance in obese humans: does it exist and what does it mean. International Journal of Obesity and Related Metabolic Disorders 22, 1159–1163 CrossRefGoogle ScholarPubMed
Banks, WA & Farrell, CL (2003) Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. American Journal of Physiology 285, E10–E15 Google Scholar
Bates, SH, Myers, MG Jr (2003) The role of leptin receptor signaling in feeding and neuroendocrine function. Trends in Endocrinology and Metabolism 14, 447–452 Google Scholar
Berthoud, HR (2002) Multiple neural systems controlling food intake and body weight. Neuroscience and Biobehavioral Reviews 26, 393–428 CrossRefGoogle ScholarPubMed
Blevins, JE, Schwartz, MW & Baskin, DG (2002) Peptide signals regulating food intake and energy homeostasis. Canadian Journal of Physiology and Pharmacology 80, 396–406 CrossRefGoogle ScholarPubMed
Bluher, S, Ziotopoulou, M, Bullen, JW, Jr, Moschos, SJ, Ungsunan, L, Kokkotou, E, Maratos-Flier, E, Mantzoros CS (2004) Responsiveness to peripherally administered melanocortins in lean and obese mice. Diabetes 53, 82–90 Google Scholar
Blundell, JE, Goodson, S & Halford, JC (2001) Regulation of appetite: role of leptin in signalling systems for drive and satiety. International Journal of Obesity and Related Metabolic Disorders 25, S29–S34 Suppl. 1 Google Scholar
Boston, BA, Blaydon, KM, Varnerin, J & Cone, RD (1997) Independent and additive effects of central POMC and leptin pathways on murine obesity. Science 278, 1641–1644 CrossRefGoogle ScholarPubMed
Burton-Freeman, B, Gietzen, DW & Schneeman, BO (1999) Cholecystokinin and serotonin receptors in the regulation of fat-induced satiety in rats. American Journal of Physiology 276, R429–R434 Google Scholar
Cai, XJ, Liu, XH, Evans, M, Clapham, JC, Wilson, S, Arch, JR, Morris, R & Williams, G (2002) Orexins and feeding: special occasions or everyday occurrence. Regulatory Peptides 104, 1–9 Google Scholar
Carvalheira, JB, Ribeiro, EB, Araujo, EP, Guimaraes, RB, Telles, MM, Torsoni, M, Gontijo, JA, Velloso, LA & Saad, MJ (2003) Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats. Diabetologia 46, 1629–1640 CrossRefGoogle ScholarPubMed
Clifton, PG (2000) Meal patterning in rodents: psychopharmacological and neuroanatomical studies. Neuroscience and Biobehavioral Reviews 24, 213–222 CrossRefGoogle ScholarPubMed
Clifton, PG, Lee, MD & Dourish, CT (2000) Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist and d -fenfluramine on feeding patterns in the rat. Psychopharmacology 152, 256–267 CrossRefGoogle Scholar
Crawley, JN (1999) The role of galanin in feeding behavior. Neuropeptides 33, 369–375 CrossRefGoogle ScholarPubMed
Eckel, LA, Langhans, W, Kahler, A, Campfield, LA, Smith, FJ & Geary, N (1998) Chronic administration of OB protein decreases food intake by selectively reducing meal size in female rats. American Journal of Physiology 275, R186–R193 Google Scholar
El-Haschimi, K, Pierroz, DD, Hileman, SM, Bjorbaek, C & Flier, JS (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. Journal of Clinical Investigation 105, 1827–1832 Google Scholar
Elmquist, JK, Bjorbaek, C, Ahima, RS, Flier, JS & Saper, CB (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. Journal of Comparative Neurology 395, 535–547 Google Scholar
Erlanson-Albertsson, C & York, D (1997) Enterostatin – a peptide regulating fat intake. Obesity Research 5, 360–372 Google Scholar
Gabriely, I, Ma, XH, Yang, XM, Rossetti, L & Barzilai, N (2002) Leptin resistance during aging is independent of fat mass. Diabetes 51, 1016–1021 CrossRefGoogle ScholarPubMed
Gloaguen, I, Costa, P, Demartis, A, Lazzaro, D, Dimarco, A, Graziani, R et al. (1997) Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance. Proceedings of the National Academy of Sciences USA 94, 6456–6461 CrossRefGoogle ScholarPubMed
Griffond, B & Baker, BI (2002) Cell and molecular cell biology of melanin-concentrating hormone. International Review of Cytology 213, 233–277 Google Scholar
Gunn, I, O'Shea, D & Bloom, SR (1997) Control of appetite – the role of glucagon-like peptide-1 (7–36) amide. Journal of Endocrinology 155, 197–200 Google Scholar
Halaas, JL, Boozer, C, Blair, West, J, Fidahusein, N, Denton, DA, Friedman JM (1997) Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proceedings of the National Academy of Sciences USA 94, 8878–8883 Google Scholar
Halford, JCG & Blundell, J (2000) Separate systems for serotonin and leptin in appetite control. Annals of Medicine 32, 222–232 Google Scholar
Hansen, MJ, Jovanovska, V & Morris, MJ (2004) Adaptive responses in hypothalamic neuropeptide Y in the face of prolonged high-fat feeding in the rat. Journal of Neurochemistry 88, 909–916 Google Scholar
Harrold, JA & Williams, G (2003) The cannabinoid system: a role in both the homeostatic and hedonic control of eating. British Journal of Nutrition 90, 729–734 Google Scholar
Hausberg, M, Morgan, DA, Chapleau, MA, Sivitz, WI, Mark, AL & Haynes, WG (2002) Differential modulation of leptin-induced sympathoexcitation by baroreflex activation. Journal of Hypertension 20, 1633–1641 Google Scholar
Haynes, AC, Chapman, H, Taylor, C, Moore, GB, Cawthorne, MA, Tadayyon, M, Clapham, JC & Arch, JR (2002) Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice. Regulatory Peptides 104, 153–159 Google Scholar
Heisler, LK, Cowley, MA, Tecott, LH, Fan, W, Low, MJ, Smart, JL et al. (2002) Activation of central melanocortin pathways by fenfluramine. Science 297, 609–611 CrossRefGoogle ScholarPubMed
Heritier, A, Charnay, Y & Aubert, ML (1997) Regional distribution of mRNA encoding the long form of leptin receptor in the mouse brain. Neuroscience Research Communications 21, 113–118 Google Scholar
Hohmann, JG, Teal, TH, Clifton, DK, Davis, J, Hruby, VJ, Han, G & Steiner, RA (2000) Differential role of melanocortins in mediating leptin's central effects on feeding and reproduction. American Journal of Physiology 278, R50–R59 Google Scholar
Hu, Z, Cha, SH, Chohnan, S & Lane, MD (2003) Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proceedings of the National Academy of Sciences USA 100, 12624–12629 CrossRefGoogle ScholarPubMed
Hulsey, MG, Lu, H, Wang, T, Martin, RJ & Baile, CA (1998) Intracerebroventricular (i.c.v.) administration of mouse leptin in rats: behavioral specificity and effects on meal patterns. Physiology and Behavior 65, 445–455 CrossRefGoogle ScholarPubMed
Kahler, A, Geary, N, Eckel, LA, Campfield, LA, Smith, FJ & Langhans, W (1998) Chronic administration of OB protein decreases food intake by selectively reducing meal size in male rats. American Journal of Physiology 275, R180–R185 Google Scholar
Kaiyala, KJ, Prigeon, RL, Kahn, SE, Woods, SC & Schwartz, MW (2000) Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49, 1525–1533 Google Scholar
Kawai, K, Sugimoto, K, Nakashima, K, Miura, H & Ninomiya, Y (2000) Leptin as a modulator of sweet taste sensitivities in mice. Proceedings of the National Academy of Sciences USA 97, 11044–11049 Google Scholar
Kelly, JF, Elias, CF, Lee, CE, Ahima, RS, Seeley, RJ, Bjorbaek, C, Oka, T, Saper, CB, Flier, JS & Elmquist, JK (2004) Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain. Diabetes 53, 911–920 Google Scholar
Kirchgessner, AL, Liu, M-T (1999) Orexin synthesis and response in the gut. Neuron 24, 941–951 CrossRefGoogle ScholarPubMed
Konturek, SJ, Konturek, JW, Pawlik, T & Brzozowski, T (2004) Brain-gut axis and its role in the control of food intake. Journal of Physiology and Pharmacology 55, 137–154 Google Scholar
Levin, BE (2000) Metabolic imprinting on genetically predisposed neural circuits perpetuates obesity. Nutrition 16, 909–915 Google Scholar
Levin, BE (2002) Metabolic sensors: viewing glucosensing neurons from a broader perspective. Physiology and Behavior 76, 397–401 Google Scholar
Lin, L, Martin, R, Schaffhauser, AO & York, DA (2001) Acute changes in the response to peripheral leptin with alteration in the diet composition. American Journal of Physiology 280, R504–R509 Google Scholar
Lin, L, Thomas, SR, Kilroy, G, Schwartz, GJ & York, DA (2003) Enterostatin inhibition of dietary fat intake is dependent on CCK-A receptors. American Journal of Physiology 285, R321–R328 Google Scholar
Maneuf, Y, Higginbottom, M, Pritchard, M, Lione, L, Ashford, MLJ & Richardson, PJ (2004) Small molecule leptin mimetics overcome leptin resistance in obese rats. Fundamental and Clinical Pharmacology 18 83 Suppl. 1 Google Scholar
Mantzoros, CS, Frederich, RC, Qu, DQ, Lowell, BB, Maratosflier, E & Flier, JS (1998) Severe leptin resistance in brown fat-deficient uncoupling protein promotor driven diphtheria-toxin-A mice despite suppression of hypothalamic neuropeptide Y and circulating corticosterone concentrations. Diabetes 47, 230–238 Google Scholar
Mark, AL, Correia, ML, Rahmouni, K & Haynes, WG (2002) Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications. Journal of Hypertension 20, 1245–1250 Google Scholar
Minokoshi, Y, Alquier, T, Furukawa, N, Kim, YB, Lee, A, Xue, B, Mu, J, Foufelle, F, Ferre, P, Birnbaum, MJ, Stuck, BJ & Kahn, BB (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 Google Scholar
Montague, CT, Farooqi, IS, Whitehead, JP, Soos, MA, Rau, H, Wareham, NJ et al. (1997) Congenital leptin deficiency is associated with severe early onset obesity in humans. Nature 387, 903–908 CrossRefGoogle ScholarPubMed
Morrison, SF (2001) Differential regulation of sympathetic outflows to vasoconstrictor and thermoregulatory effectors. Annals of the New York Academy of Sciences 940, 286–298 Google Scholar
Niswender, KD & Schwartz, MW (2003) Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Frontiers in Neuroendocrinology 24, 1–10 Google Scholar
Obici, S, Feng, Z, Arduini, A, Conti, R & Rossetti, L (2003) Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nature Medicine 9, 756–761 Google Scholar
Obici, S, Feng, Z, Karkanias, G, Baskin, DG & Rossetti, L (2002) Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nature Neuroscience 5, 566–572 Google Scholar
Obici, S & Rossetti, L (2003) Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 144, 5172–5178 CrossRefGoogle ScholarPubMed
Pico, C, Oliver, P, Sanchez, J & Palou, A (2003) Gastric leptin: a putative role in the short-term regulation of food intake. British Journal of Nutrition 90, 735–741 Google Scholar
Rahmouni, K, Haynes, WG, Morgan, DA & Mark, AL (2003) Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 41, 763–767 Google Scholar
Robbins, TW & Everitt, BJ (1996) Neurobehavioural mechanisms of reward and motivation. Current Opinion in Neurobiology 6, 228–236 CrossRefGoogle ScholarPubMed
Rodgers, RJ, Halford, JCG, Nunes, RL, Canto, AL, Piper, DC, Arch, JRS, Upton, N, Porter, RA, Johns, A & Blundell, J (2001) SB-334867, a selective orexin-1 receptor antagonist enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. European Journal of Neuroscience 13, 1444–1452 Google Scholar
Routh, VH (2002) Glucose-sensing neurons: are they physiologically relevant. Physiology and Behavior 76, 403–413 Google Scholar
Saper, CB, Chou, TC & Elmquist, JK (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 Google Scholar
Scarpace, PJ, Matheny, M, Zolotukhin, S, Tumer, N & Zhang, Y (2003) Leptin-induced leptin resistant rats exhibit enhanced responses to the melanocortin agonist MT II. Neuropharmacology 45, 211–219 Google Scholar
Scarpace, PJ & Tumer, N (2001) Peripheral and hypothalamic leptin resistance with age-related obesity. Physiology and Behavior 74, 721–727 Google Scholar
Seals, DR & Bell, C (2004) Chronic sympathetic activation: consequence and cause of age-associated obesity. Diabetes 53, 276–284 Google Scholar
Smart, D, Haynes, AC, Williams, G & Arch, JR (2002) Orexins and the treatment of obesity. European Journal of Pharmacology 440, 199–212 Google Scholar
Stanley, S, Wynne, K & Bloom, S (2004) Gastrointestinal satiety signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY, and pancreatic polypeptide. American Journal of Physiology 286, G693–G697 Google ScholarPubMed
Strubbe, JH & Woods, SC (2004) The timing of meals. Psychological Review 111, 128–141 Google Scholar
Thibault, L & Booth, DA (1999) Macronutrient-specific dietary selection in rodents and its neural bases. Neuroscience and Biobehavioral Reviews 23, 457–528 Google Scholar
Thornton-Jones, ZD, Vickers, SP & & Clifton, PG (2004) The cannabinoid CB1 receptor antagonist SR 141716A reduces motivation for feeding behaviour. http://www.pa2online.org/articleindex.html Google Scholar
Tups, A, Ellis, C, Moar, KM, Logie, TJ, Adam, CL, Mercer, JG & Klingenspor, M (2004) Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression. Endocrinology 145, 1185–1193 CrossRefGoogle ScholarPubMed
Van Heek, M, Compton, DS, France, CF, Tedesco, RP, Fawzi, AB, Graziano, MP, Sybertz, EJ, Strader, CD, Davis, HR Jr (1997) Diet-induced obese mice develop peripheral, but not central, resistance to leptin. Journal of Clinical Investigation 99, 385–390 Google Scholar
Widdowson, PS, Upton, R, Buckingham, RE, Arch, JRS & Williams, G (1997a) Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity. Diabetes 46, 1782–1785 Google Scholar
Widdowson, PS, Upton, R, Henderson, L, Buckingham, RE, Wilson, S & Williams, G (1997b) Reciprocal regional changes in brain NPY receptor density during dietary restriction and dietary-induced obesity in the rat. Brain Research 774, 1–10 Google Scholar
Williams, G & Bloom, SR (1987) The search for a hormonal switch for obesity. British Medical Journal 294, 1686–1687 Google Scholar
Woods, SC & Seeley, RJ (2001) Insulin as an adiposity signal. International Journal of Obesity and Related Metabolic Disorders 25, S35–S38 Suppl. 5 Google Scholar
Wortman, MD, Clegg, DJ, D'Alessio, D, Woods, SC & Seeley, RJ (2003) C75 inhibits food intake by increasing CNS glucose metabolism. Nature Medicine 9, 483–485 Google Scholar
Wynne, K, Stanley, S & Bloom, S (2004) The gut and regulation of body weight. Journal of Clinical Endocrinology and Metabolism 89, 2576–2582 Google Scholar