Nuevas Terapias para la Obesidad Como controlar el Apetito y la Saciedad La visión de un Clínico
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- Nuevas Terapias para la Obesidad. Como controlar el apetito y la saciedad. La visión de un clínico - Dr. Q. Raúl Caminos Torres (Comité Ejecutivo FLASO)
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Nuevas Terapias para la Obesidad Como controlar el Apetito y la Saciedad La visión de un Clínico
- 2. • Disminuir el consumo de comida incrementando la saciedad, reduciendo el apetito y elevando el sentido de gratificación • Disminuir la absorción de energia del área gastrointestinal al resto de los tejidos. • Reducir la grasa corporal estimulando el gasto energético, o inhibiendo el suministro de energía al tejido adiposo • Regular la actividad inflamatoria del tejido adiposo • Modular la distribución de la grasa corporal, el flujo de energía al tejido adiposo, o simulando el gasto energético por ejercicio
- 3. Impacto hedónico GUSTAR QUERER APRENDER Motivación Asociaciones, predicciones
- 5. Visión Músculos Emoción Volición Centros de integración Cerebrales Factores Genéticos Señales metabólicas Tracto Gastrointestinal Páncreas Audición Tejido adiposo Brain integratory centres
- 8. Tres cohortes con dos dosis diarias por 14 días de PSN821: a) 250mg como monoterapia [n=7], b) 250mg + Metformina [n=6], c) 500mg + Met [n=7]) y placebo [n=5]. Se observaron cambios en la Glucosa en ayunas que fueron aparentes En todos los grupos ↑Secreción de tratamiento de Insulina ↓ activo: Vaciamiento -2.0, gástrico -2.3, -2.1 ↓ mmol/Ingesta L de respectivamente. Estimulada El grupo por placebo glucosa ↓ -0.7 Glucagon mmol/L. alimentos Después de las comidas se apreciaron reducciones en la exposición a la glucosa PROTECCIÓN (E, AUC, reactive METABOLISMO AUCDE ), que fueron mayores en max0-5hr0-5hrPÉRDIDA DE las cohortes DE de PSN821 que con placebo. GLUCOSA PESO CÉLULAS β MEJORADO PSN821 500 mg produjo reducciones de -40 % en ingesta energética a los 14 dias, con pérdidas de peso de -2.4, -1.8, -2.1 kg, (placebo -1.1 kg). PROGRESIÓN A LA DM MÁS LENTA Goodman, M. et al: ADA 2011. “The Novel GPR119-Receptor Agonist PSN821 Shows Glucose Lowering and Decreased Energy Intake in Patients with T2DM after 14 Days Treatment” En el Simposio “Pharmacologic Treatment of Diabetes—Novel Therapies”
- 11. • INHIBIDORES DE LA LIPASA PANCREATICA Orlistat, Cetilistat, ORLISTAT Promedio de Pérdida de peso ≥ 5 % en 1 año= 54,3 % Promedio de Pérdida de peso ≥ 10 % en 1 año= 24,7 %
- 12. • INHIBIDORES DE LA LIPASA PANCREATICA Orlistat, Cetilistat, • INHIBIDORES DE LA INTESTINAL MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN ( MTP, Forma enterocítica) Necesaria para el ensamblaje de Apoliproteina B Lomitapide, SLx-4090, JNJ-16269110, JT-130 Efectos de JTT-130 sobre el Vaciamiento gástrico en ratas Sprague-Dawley. Takahiro H. et al: J Pharmacology Experimental Therapeutics. 2011;336(3): 850-856
- 13. • INHIBIDORES DE LA LIPASA PANCREATICA Orlistat, Cetilistat, • INHIBIDORES DE LA INTESTINAL MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN ( MTP, Forma enterocítica) Necesaria para el ensamblaje de Apoliproteina B Lomitapide, SLx-4090, JNJ-16269110 • INHIBIDORES DE LA DIACIL GLICEROL O-ACILTRANSFERASA (DGAT) Cataliza el paso final de la síntesis de Triglicéridos PF-04620110 • INHIBIDORES DE LA 2-ACIL GLICEROL O-ACILTRANSFERASA 2 (MOGT) Cataliza la formación de Diacilglicerol desde 2-Monoacilglicerol/ AcilCoA. PF-04620110 • MODULADORES DE LA FLORA INTESTINAL
- 16. INHIBIDORES DE LA LOW AFFINITY SODIUM-DEPENDENT GLUCOSE COTRANSPORTER (SGLT2) Canaglifoxin, Empaglifoxin, Remoglifoxin, SGLT-2 Segmentos 1 y 2 (>90 % de Glucosa reabsorbida) SGLT-1 Segmento 3 (10 % de Glucosa restante)
- 19. Ayuno NAD+/NADH Calorías Resveratrol?
- 22. Tejido Adiposo β-Oxidación Grasa corporal Lipogénesis Infiltración de macrófagos
- 24. AREAS DEL HIPOTALAMO NTS:= Nucleo del tracto solitario ARC= Nucleo Arcuato LHA = Area Lateral hipotalámica VMN = N.Ventromedial PVN = N.Paraventricular DMN= N.Dorsomedial
- 25. En el hipotálamo existen Neuronas que expresan actividad orexigénica y anorexigénica Anorexigénicos CCK = Colecistoquinina GLP = Glucagon-like Peptide PYY = Péptido YY Leptin= Leptina Glucagon POMC= Pro Opio Melanocortin α-MSH= α-Melanocite Diencefalo, hipófisis, adrenales Respuestas vagales a la ingesta Stimulating Hormone CRF= Corticotrophin Releasing Factor Neurotensin Orexigénicos OXM= Oxintomodulina Ghrelin= Grelina AgRP= Agouti Related Prot. Orexin NPY= Neuropéptido Y MCH= Melanin Concentrating Hormone
- 26. Apetito Saciedad
- 27. AYUNO INGESTA EN EXCESO —Liberación estomacal de Ghrelina y Secreción de Leptina Liberación estomacal de Ghrelina y Secreción de Leptina Activación hipotalámica de NPY / AgRP y Producción de α-MSH Activación hipotalámica de NPY / AgRP y Producción de α-MSH Gasto Energético y Tendencia a Ia ingesta de alimentos Gasto Energético y Tendencia a Ia ingesta de alimentos
- 28. 5-HT Serotonin (5-hydroxytryptamine) 11β-HSD1 11-β Hydroxysteroid Dehydrogenase type 1 AgRP Agouti-Related Protein β3AR β3-Adrenoceptors BAT Brown adipose tissue CART Cocaine-Amphetamine-Regulated Transcript CB1 Cannabinoid receptor type 1 CCK Cholecystokinin DGAT Diacylglycerol O-acyltransferase DPP-IV Dipeptidyl Peptidase IV EEC Entero-endocrine cell GABA Gamma-Amino Butyrate GH Growth Hormone
- 29. GIP Glucose-Induced Polipeptide GLP-1 Glucagon-like peptide 1 HPA(-axis) Hypothalamic Pituitary Adrenal (-axis) MCH Melanine-concentrating hormone MSH Melanocyte-stimulating hormone MTP Microsomal Triglyceride transfer protein NPY Neuropeptide Y OXM Oxyntomodulin POMC Pro-Opiomelanocortin PP Pancreatic Polypeptide PPAR γ Peroxisome Proliferator-activated receptor- g PYY Peptide YY TRPV Type 1 transient receptor potential cation channel V type 1
- 30. Nombre del medicamento Desarrollador Mecanismo de acción Otras Indicaciones Exenatide; Byetta Amylin Agonista del Glucagon-like peptide 1; secretagogo de insulina Diabetes tipo 1; Diabetes tipo 2 ZYO1 Zydus Cadila Antagonista Cannabinoid CB1 Diabetes TTP-435; TTP-2435 TransTech Inhibidor de la Agouti related Protein TM30339 7TM Pharma Agonista del Neuropeptide Y4 Velneperit; S-2367 Shionogi Antagonista Neuropéptido Y5 Obinepitide; TM-30338 7TM Pharma Agonista Neuropéptido Y2 / Y4 AC-162352; PYY3-36 Amylin Agonista del Neuropeptide Y4 Tesofensine NeuroSearch Inhibidor de la captación/ recaptación de Serotonina, norepinefrina y dopamina Disquinesias; diabetes, tipo 2 Pramlintide; Normylin; Symlin; tripro-amylin Amylin Agonista de Amilina; secretagogo de insulina Diabetes tipo 1; Diabetes tipo 2 Metreleptin + Pramlintide Amylin Agonista de Amilina; agonista del receptor de Leptina Davalintide; AC-2307; Amylin Agonista de Amilina; secretagogo de insulina Diabetes
- 31. Nombre del medicamento Desarrollador Mecanismo de acción Otras Indicaciones LY-377604; LY-362884 Eli Lilly Agonista del β-Adrenoreceptor DM-2; Vejiga hiperactiva N-5984; KRP-204 Kyorin Agonista del β-Adrenoreceptor DM-2; Vejiga hiperactiva Eprotirome; KB-141; KB- Hiperlipidemia; Sindr. Karo Bio Agonista de T-4 2115; STRMs Metabólico Bupropion SR plus zonisamide IR; Empatic; Excalia Orexigen Inhibidor de la recaptación de Dopamine; Agonista del receptor del GABA Zonisamide; Excegran; Tremode; Trerief; Zonegran Dainippon Sumitomo Pharma Agonista del receptor del GABA Epilepsia; Enfermedad de Parkinson; migraña; psicosis; depresion BMS-830216; BMS 819881 prodrug; Bristol-Myers Squibb Antagonista de MCH-1 Histalean; OBE-101 OBEcure Agonista del Histamine H1 R; Antagonista del R de Histamina H3 ALS-L1023 AngioLab Inhibidor de la Angiogenesis Inhibidor de la MMP
- 32. Blanco predominante Mecanismo de Acción Compuestos Dopamina/Noerepinefrina/ Serotonina Inhición de la captación Bupropion, Tesofensine, Sibutramina Activación de la liberación Fentermina GABA Estimulación de la actividad de GABA Topiramato (Con Fentermina), Zonisamida (Con Bupropion) Receptor de Serotonina (5-HT2c) Agonista Lorcaserin Receptor de Serotonina (5-HT6) Agonista Varios Receptor de MC-4 Agonista En Fase Preclínica Receptor de MCH-1 Antagonista NGD-47125 Receptor de Histamina (H3) Antagonista En Fase Preclínica Receptor de NPY (Y5) Antagonista Velneperit AgRP Inhibición TTP-435 TTPIB Inhibición Trodusquemina
- 34. 0 1 2 3 4 5 6 Estudio Fase III de 1 año de duración (extensión a 2 años) - 2.1 - 5.8 p < 0.001 Placebo Lorcaserin Variación de Peso (Kgs) J. Pharmacol. Exp. Ther 2008; 325 (2): 577 Bryson A, et al Br. J. Clin. Pharmacol 2009; 67(3), 309 Expert Rev Clin Pharmacol 2010; 3(1): 73 ≥5% ≥10% 50 40 30 20 10 0 20.3 47.5 7.7 22.6 % de pacientes con Pérdida de peso
- 35. Alucinaciones Agitación Coma Presión arterial inestable Taquicardia Hipertermia Contracturas musculares Incoordinación de movimientos Manifestaciones gastrointestinales
- 36. EQUIP: Estudio aleatorizado doble ciego con dieta disminuida en 500 Kcal. X 1 año. 67 % perdió 5 % de peso. 47 % perdió 10 % CONQUER :Estudio aleatorizado doble ciego con dieta disminuida en 500 Kcal. X 56 semanas. Obesos con comorbilidades 62 % perdió 5 % de peso. 37 % perdió 10 % SEQUEL: Estudio aleatorizado doble ciego con dieta disminuida en 500 Kcal. En completadores de CONQUER 79 % perdió 5 % de peso. 52 % perdió 10 % FORTRES: Evaluar Teratogenésis. El doble de casos con paladar hendido vs placebo
- 37. Estudio Fase III / Prospectivo / Controlado con Placebo / ITT - LOCF USA / 756 pacientes / IMC > 30 (Promedio 36.3) / 28 semanas 0 2 4 6 8 10 Placebo Qsymia (7.5 + 46 mgs) Qsymia (15 + 92 mgs) - 1.7 - 8.5 p≤ 0.01 Variación de Peso (%) ≥5% ≥10% 70 60 50 40 30 20 10 0 15 62 7 39 Pérdida percentual de peso - 9.2 p≤ 0.01 66 41 Expert Rev Clin Pharmacol. 2010; 3(1): 73
- 38. Boca seca Insomnio Hipertensión Pulmonar Primaria Palpitaciones Taquicardia Hipertensión Arterial Eventos Isquémicos CONTRAINDICACIONES: Enf. Cardiovascular, Inhibidores de MAO, Hipertiroidismo, Glaucoma, Estados de Agitación, Embarazo
- 39. (Efectos por inhibición de la Anhidrasa Carbónica) Parestesias distales y periorbitales Acidosis metabólica Acidosis Tubular Renal Nefrolitiasis Declinación cognitiva Pérdida de memoria Mareos Hipohidrosis
- 40. LORCASERIN Promedio de Pérdida de peso ≥ 5 % en 1 año= 43,4 % FENTERMINA + TOPIRAMATO Promedio de Pérdida de peso ≥ 10 % en 1 año= 18,4 % Promedio de Pérdida de peso ≥ 5 % en 1 año: (3,7+15 mg)= 44,9 % (7,5+46 mg)= 62,0 % (15+92 mg)= 68,3 % Promedio de Pérdida de peso ≥ 10 % en 1 año: (3,7+15 mg)= 18,8 % (7,5+46 mg)= 37,0 % (15+92 mg)= 47,6 %
- 42. GLP-1 es secretado por las células L del íleon al ingerir alimento Hipotálamo: Promueve saciedad y reduce apetito Hígado: Glucagón y reduce producción de glucosa Estómago: vaciamiento gástrico Celulas Beta: secreción de Insulina (dependiente de glicemia) Células Alfa: Secreción posprandial de Glucagón Flint A, et al: J Clin Invest. 1998;101:515-520.; Larsson H, et al: Acta Physiol Scand. 1997;160:413-422.; Nauck MA, et al: Diabetologia. 1996;39:1546-1553.; Drucker DJ: Diabetes. 1998;47:159-169.
- 43. SEÑALES OREXIGENICAS SEÑALES ANOREXIGENICAS SEÑALES ANOREXIGENICAS
- 44. Anabólico/ orexigénico Catabólico/ Anorexigénico Catabólico Anabólico Cambios en el ingreso y pérdida energética Leptina
- 47. • El 35 % de los pacientes recibiendo el medicamento deben haber perdido un mínimo de 5% del peso corporal, comparado con el peso al inicio del ensayo • Ese grupo debe incluir al menos el doble de individuos que el número de pacientes que lograron una pérdida de peso similar en el grupo placebo • Alternativamente, el tratamiento debe resultar en una pérdida de un 5% del peso corregido vs placebo
Notas del editor
- Molecular targets for antiobesity pharmacotherapeutics outside the central nervous system. In the intestine, the inhibition of gastric/pancreatic lipase reduces triglyceride hydrolysis and lipid absorption. Within the pancreas, the opening of K+-ATP channels reduces insulin secretion, leading to enhanced nutrient catabolism and reduced nutrient storage. In adipose tissue, the activation of both β3AR and GHR induce lipolysis. Also, inhibition of 11β-HSD1, which converts inactive cortisone to active cortisol, may induce weight loss, given that high cortisol levels are associated with increased fat accumulation. Activated adipocytes also produce an array of vascular growth factors and MMPs that induce an expansion of the capillary bed, aiding the growth of adipose tissue. Inhibition of angiogenesis within the adipose tissue may therefore be effective in reducing adiposity. Finally, weight loss may be achieved by modulation of cellular metabolism through the activation of SIRT1, which (i) enhances fat mobilization and lipolysis by binding to PPARγ in adipocytes, thereby repressing the expression of PPAR-γ-regulated genes, including those mediating fat storage, and (ii) induces the expression of mitochondrial genes involved in oxidative metabolism and fatty acid oxidation within the liver and skeletal muscle through the activation of PGC-1α. Blue arrow, activating; red arrow, inhibiting. β3AR, β3-adrenergic receptor; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; GH, growth hormone; GHR, growth hormone receptor; MMP, matrix metalloprotease; NE, norepinephrine; PGC-1α, peroxisome proliferator–activated receptor-γ co-activator; PPARγ, peroxisome proliferator–activated receptor-γ; SIRT1, sirtuin 1.
- The K-ATP channel comprises two subunits: The Kir6.2 subunit The sulphonylurea-receptor subunit (SUR-1 in pancreatic β-cell, SUR-2A in cardiac and skeletal muscle). Note that closure of the K-ATP channel by sulphonylureas or glucose sensing causes the depolarization that triggers insulin release. Diazoxide is a K-ATP channel opener. The effects shown are amplified by other mechanisms not shown, including incretin effects of GLP-1. The presence of additional mechanisms explains why glucose-dependent insulin secretion persists despite high-dose SU treatment.
- Molecular targets for antiobesity pharmacotherapeutics outside the central nervous system. In the intestine, the inhibition of gastric/pancreatic lipase reduces triglyceride hydrolysis and lipid absorption. Within the pancreas, the opening of K+-ATP channels reduces insulin secretion, leading to enhanced nutrient catabolism and reduced nutrient storage. In adipose tissue, the activation of both β3AR and GHR induce lipolysis. Also, inhibition of 11β-HSD1, which converts inactive cortisone to active cortisol, may induce weight loss, given that high cortisol levels are associated with increased fat accumulation. Activated adipocytes also produce an array of vascular growth factors and MMPs that induce an expansion of the capillary bed, aiding the growth of adipose tissue. Inhibition of angiogenesis within the adipose tissue may therefore be effective in reducing adiposity. Finally, weight loss may be achieved by modulation of cellular metabolism through the activation of SIRT1, which (i) enhances fat mobilization and lipolysis by binding to PPARγ in adipocytes, thereby repressing the expression of PPAR-γ-regulated genes, including those mediating fat storage, and (ii) induces the expression of mitochondrial genes involved in oxidative metabolism and fatty acid oxidation within the liver and skeletal muscle through the activation of PGC-1α. Blue arrow, activating; red arrow, inhibiting. β3AR, β3-adrenergic receptor; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; GH, growth hormone; GHR, growth hormone receptor; MMP, matrix metalloprotease; NE, norepinephrine; PGC-1α, peroxisome proliferator–activated receptor-γ co-activator; PPARγ, peroxisome proliferator–activated receptor-γ; SIRT1, sirtuin 1.
- Effect of long-term orlistat therapy on body weight Figure 2—Weight loss (means SEM) during 4 years of treatment with orlistat plus lifestyle changes or placebo plus lifestyle changes in obese patients (LOCF data). XENDOS This figure shows the results of a 4-year randomized controlled trial, conducted in over 3000 obese subjects, that compared orlistat therapy plus lifestyle intervention with placebo therapy plus lifestyle intervention [1]. The lowest body weight was achieved during the first year, and was greater in the orlistat-treated group (11% weight loss) than in the placebo-treatment group (6% weight loss). Subjects regained weight during the remainder of the trial, so orlistat-treated subjects had lost 6.9% and placebo-treated subjects had lost 4.1% of their initial body weight at the end of 4 years. Orlistat therapy also resulted in a 37% reduction in the cumulative incidence of new-onset type 2 diabetes, primarily by preventing the development of diabetes in patients who had impaired glucose tolerance Torgenson JS, Boldrin MN, Hauptman J, et al. XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study. Diabetes Care 2004; 27: 155-161.
- Molecular targets for antiobesity pharmacotherapeutics outside the central nervous system. In the intestine, the inhibition of gastric/pancreatic lipase reduces triglyceride hydrolysis and lipid absorption. Within the pancreas, the opening of K+-ATP channels reduces insulin secretion, leading to enhanced nutrient catabolism and reduced nutrient storage. In adipose tissue, the activation of both β3AR and GHR induce lipolysis. Also, inhibition of 11β-HSD1, which converts inactive cortisone to active cortisol, may induce weight loss, given that high cortisol levels are associated with increased fat accumulation. Activated adipocytes also produce an array of vascular growth factors and MMPs that induce an expansion of the capillary bed, aiding the growth of adipose tissue. Inhibition of angiogenesis within the adipose tissue may therefore be effective in reducing adiposity. Finally, weight loss may be achieved by modulation of cellular metabolism through the activation of SIRT1, which (i) enhances fat mobilization and lipolysis by binding to PPARγ in adipocytes, thereby repressing the expression of PPAR-γ-regulated genes, including those mediating fat storage, and (ii) induces the expression of mitochondrial genes involved in oxidative metabolism and fatty acid oxidation within the liver and skeletal muscle through the activation of PGC-1α. Blue arrow, activating; red arrow, inhibiting. β3AR, β3-adrenergic receptor; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; GH, growth hormone; GHR, growth hormone receptor; MMP, matrix metalloprotease; NE, norepinephrine; PGC-1α, peroxisome proliferator–activated receptor-γ co-activator; PPARγ, peroxisome proliferator–activated receptor-γ; SIRT1, sirtuin 1.
- SIRT1 is involved in many functions in the liver. It controls key aspects of lipid and glucose metabolism through interaction with transcription factors. SIRT1 is activated in response to fasting, calorie restriction, changes in NAD+/NADH levels and by the polyphenol resveratrol.
- SIRT1 controls many aspects of lipid metabolism and fat cell maturation. SIRT1 represses the PPARγ nuclear receptor, thus down-regulating adipocyte differentiation and maturation. Loss of SIRT1 leads to increased adipose tissue macrophages and elevated inflammation.
- Humoral and nutritional crosstalk between peripheral tissues and the brain. To adapt to daily variations in energy balance, our bodies sense and integrate information about energy availability that is conveyed to the brain by peripheral hormones (for example, pancreatic polypeptide (PP), cholecystokinin (CCK) and peptide YY (YY)) and nutrients (for example, glucose, free fatty acids (FFA) and amino acids (AA)). These molecules regulate feeding behaviour by acting on neurons in the hypothalamus and the brainstem. During periods of satiety, the body works towards storage of the acquired nutrients. Satiety is associated with increased sympathetic activity, which promotes both insulin release by the pancreas (and thus stimulates glucose storage in the liver and muscle) and fat deposition (which leads to a rise in leptin levels). Food ingestion results in a release of incretins by the gut. These include glucagon-like peptide 1 (GLP1), which stimulates the pancreas to secrete insulin; both GLP1 and insulin are thought to reduce food intake by acting directly on the brain. In pancreatic β‑cells, the hormone amylin is released together with insulin in response to a meal. Amylin is a potent satiety signal, which inhibits digestive secretion and slows gastric emptying. The precise brain targets of amylin are not known, but include the area postrema in the brainstem and the lateral hypothalamus. Conversely, during periods of hunger, the hypothalamus regulates the activity of the autonomic nervous system to promote fat release from white adipose tissue and trigger gluconeogenesis in the liver. These changes in peripheral nutrient levels lead to a decrease in the levels of thyroid hormones, insulin and leptin, and to an increase in the level of ghrelin and corticosteroids, which increase food-seeking behaviour through their effect on the brain. The hormones and peptides mentioned above are only a few among many molecules that are thought to be involved in the regulation of energy balance. In the brain, the hypothalamus (small boxed area in mid-sagittal view of the brain) contains two critical subsets of neurons (enlarged in boxed area): the neuropeptide Y/agouti-relatedprotein/γ-amino butyric acid (NPY/AgRP/GABA) neurons, which, when activated owing to decreasing glucose and leptin levels and increasing ghrelin levels, promote hunger and appetite, in part by suppressing the activity of neighbouring pro-opiomelanocortin (POMC) neurons, and antagonizing melanocortin 4 (MC4) receptors in target areas. Increasing glucose and leptin levels with subsiding ghrelin availability inhibit NPY/AgRP neurons and activate POMC cells, which in turn lead to satiety. The POMC neurons also co-express the cocaine- and amphetamine-regulated transcript (CART), and when activated they release α-melanocyte-stimulating hormone (α-MSH) in target regions, which functions as an endogenous agonist of MC4 receptors and promotes satiety. Research into this complex system continues to identify new candidates that could be pharmacologically targeted to regulate energy balance263.
- Endogenous signaling of appetite-regulating hormones, neuropeptides, and neurotransmitters and the drugs that target these pathways. The arcuate nucleus of the hypothalamus is the primary neural signaling site for peripheral satiety hormones. It is composed of two primary types of appetite-regulating neurons: (i) those expressing the anorexigenic neuropeptides POMC and CART and (ii) those expressing the orexigenic neuropeptides AgRP and NPY. There is communication between the hypothalamus and the brainstem, particularly the DVC, which is targeted by several satiety hormones and also receives satiety signals from vagal afferents from the gastrointestinal tract. NPY/AgRP and POMC/CART neurons act on second-order neurons of the hypothalamus, including the neurons of the PVN that express CRH and TRH and the neurons of the LHA that express orexin-concentrating hormone and MCH. These second-order neurons target higher brain centers to induce either suppression or stimulation of the appetite. Monoamine neurotransmission is also important in appetite regulation because central histamine and serotonin signaling suppress appetite. Central noradrenergic and dopaminergic signaling (not shown) also reduces appetite. Blue line, activating; red line, inhibiting. AgRP, agouti-related peptide; CART, cocaine- and amphetamine-regulated transcript; CCK, cholecystokinin; CCK1R, cholecystokinin receptor-1; CTR, calcitonin receptor; CRH, corticotropin-releasing hormone; DVC, dorsal vagal complex; GHSR, growth hormone secretagogue receptor; GLP1, glucagon-like peptide 1; GLP1R, glucagon-like peptide 1 receptor; H1R, histamine receptor-1; H3R, histamine receptor-3; 5HT2c, 5-hydroxytryptamine receptor-2C; LepR, leptin receptor; LHA, lateral hypothalamic area; MC3/4R, melanocortin 3/4 receptor; MCH, melanin concentrating hormone; MCH1R, melanin-concentrating hormone receptor 1; αMSH, α-melanocyte-stimulating hormone; NPY, neuropeptide Y; µ-OR, µ-opioid receptor; ORX, orexin; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; PVN, paraventricular nucleus; TRH, thyrotropin-releasing hormone; Y1R, Y1 receptor; Y2R, Y2 receptor; Y4R, Y4 receptor.
- Leptin acts directly on arcuate nucleus neurons coexpressing NPY and AgRP, and POMC and CART, via the ObRb form of the leptin receptor expressed on these cells. The former neurons stimulate anabolic and orexigenic effects and are suppressed by leptin; the latter neurons stimulate catabolic and anorexic actions, promoting weight loss. Downstream, these neurons target neurons expressing melanocortin 4 receptors that are activated by the POMC product α MSH, and inhibited by the neuropeptide AgRP. Activation of these neurons promotes catabolism,via Brain-derived neurotrophic factor, by reducing food intake and increasing energy expenditure. (Reprinted from Cell, 116:337–50, 2004.) Leptin, an appetite-suppressing hormone secreted by fat cells, is "a truly critical player in the field," says Cummings. Its discovery in 19944 is widely credited with starting this golden age of research. "If you asked people about adipose tissue 10 years ago, everyone said, well, it's a tedious insulator and store for fat. And that was the sum of world knowledge," says Seckl. "Now we have a dozen new hormones which come out of it." Leptin receptors were soon identified in two populations of neurons in the arcuate nucleus of the hypothalamus. One population produces the appetite-stimulating neuropeptides NPY (neuropeptide Y) and AgRP (agouti-related protein), which are suppressed by leptin, while POMC (proopiomelanocortin) and CART (cocaine- and amphetamine-related transcript) neurons suppress appetite and are activated by leptin. As fat stores are reduced, so is the amount of circulating leptin, causing appetite to increase.