Neuroadrenergic dysfunction in obesity: an overview of the effects of weight loss

Purpose of review The prevalence of obesity is rising to epidemic proportions worldwide, and in tandem so is that of type 2 diabetes. Neuroadrenergic abnormalities, comprising increased resting sympathetic nervous system activity and blunted sympathetic neural responsiveness are recognized features of metabolic syndrome obesity, which contribute importantly to both the pathophysiology and adverse clinical prognosis of this high-risk population. Weight loss is recommended as first-line treatment for obesity. This review examines the effects of nonpharmacological weight loss on sympathetic nervous system function under basal and stimulated conditions. Recent findings Human weight loss trials show that even moderate weight reduction is accompanied by significant attenuation in resting whole-body norepinephrine spillover rate and muscle sympathetic nerve activity, an improvement in cardiac autonomic modulation, and a reversal of blunted sympathetic responsiveness at both peripheral and central nervous system levels. Recent findings underscore the relevance of insulin resistance in mediating blunted sympathetic responsiveness to endogenous hyperinsulinemia induced by glucose ingestion. Impaired insulin transport across the blood–brain barrier may be one mechanism mediating these effects. Weight loss reverses blunted sympathetic responsiveness to glucose, which has implications for postprandial energy expenditure and body weight homeostasis. Summary The autonomic dysfunction of obesity is reversible with weight loss, highlighting the importance of lifestyle intervention as a key therapeutic modality.

[1]  Mathias Baumert,et al.  Short-term heart rate variability and cardiac norepinephrine spillover in patients with depression and panic disorder. , 2009, American journal of physiology. Heart and circulatory physiology.

[2]  M. Esler,et al.  Sympathetic activation in chronic renal failure. , 2009, Journal of the American Society of Nephrology : JASN.

[3]  L. Keltikangas-Järvinen,et al.  Metabolic syndrome and short‐term heart rate variability in young adults , 2009, Diabetic medicine : a journal of the British Diabetic Association.

[4]  I. Velasco,et al.  Gastric Bypass and Cardiac Autonomic Activity: Influence of Gender and Age , 2009, Obesity surgery.

[5]  G. Grassi,et al.  European Society of Hypertension Working Group on Obesity Obesity-induced hypertension and target organ damage: current knowledge and future directions. , 2009, Journal of hypertension.

[6]  Sho-ichi Yamagishi,et al.  Higher heart rate may predispose to obesity and diabetes mellitus: 20-year prospective study in a general population. , 2009, American journal of hypertension.

[7]  P. Nestel,et al.  Weight Loss May Reverse Blunted Sympathetic Neural Responsiveness to Glucose Ingestion in Obese Subjects With Metabolic Syndrome , 2009, Diabetes.

[8]  N. Nguyen,et al.  Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: findings from the National Health and Nutrition Examination Survey, 1999 to 2004. , 2008, Journal of the American College of Surgeons.

[9]  M. Esler,et al.  Mediators of sympathetic activation in metabolic syndrome obesity , 2008, Current hypertension reports.

[10]  G. Mancia,et al.  Multiple sampling improves norepinephrine reproducibility in essential hypertension: a comparison with the microneurographic technique , 2008, Journal of hypertension.

[11]  T. A. Aksnes,et al.  Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study. , 2008, Metabolism: clinical and experimental.

[12]  W. Banks,et al.  Starvation and triglycerides reverse the obesity-induced impairment of insulin transport at the blood-brain barrier. , 2008, Endocrinology.

[13]  G. Grassi.  Qualitative assessment of sympathetic neural drive in cardiometabolic disease: a new challenge. , 2007, Hypertension.

[14]  M. Esler,et al.  Differing Pattern of Sympathoexcitation in Normal-Weight and Obesity-Related Hypertension , 2007, Hypertension.

[15]  R. Kronmal,et al.  The relationship of heart rate and heart rate variability to non‐diabetic fasting glucose levels and the metabolic syndrome: The Cardiovascular Health Study , 2007, Diabetic medicine : a journal of the British Diabetic Association.

[16]  M. Lenhard,et al.  An overview of the effect of weight loss on cardiovascular autonomic function. , 2007, Current diabetes reviews.

[17]  Jason U Tilan,et al.  Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome , 2007, Nature Medicine.

[18]  C. May,et al.  Increased cardiac sympathetic nerve activity in heart failure is not due to desensitization of the arterial baroreflex. , 2007, American journal of physiology. Heart and circulatory physiology.

[19]  G. Mancia,et al.  The sympathetic nervous system and the metabolic syndrome. , 2007, Journal of hypertension.

[20]  M. Sivananthan,et al.  Relationship Between Central Sympathetic Drive and Magnetic Resonance Imaging–Determined Left Ventricular Mass in Essential Hypertension , 2007, Circulation.

[21]  G. Mancia,et al.  Age and target organ damage in essential hypertension: role of the metabolic syndrome. , 2007, American journal of hypertension.

[22]  G. Mancia,et al.  Metabolic Syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) Study: Daily Life Blood Pressure, Cardiac Damage, and Prognosis , 2007, Hypertension.

[23]  J. Born,et al.  Low cerebrospinal fluid insulin levels in obese humans , 2006, Diabetologia.

[24]  Yoon-Ho Choi,et al.  Metabolic Syndrome Is Associated with Delayed Heart Rate Recovery after Exercise , 2006, Journal of Korean medical science.

[25]  Thomas D. Giles,et al.  Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[26]  S. Kjeldsen,et al.  Arterial plasma noradrenaline predicts left ventricular mass independently of blood pressure and body build in men who develop hypertension over 20 years , 2006, Journal of hypertension.

[27]  Y. Nakaya,et al.  Relationships between thermic effect of food, insulin resistance and autonomic nervous activity. , 2006, The journal of medical investigation : JMI.

[28]  P. Nestel,et al.  Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome. , 2005, The Journal of clinical endocrinology and metabolism.

[29]  P. Arner,et al.  Prospective and controlled studies of the actions of insulin and catecholamine in fat cells of obese women following weight reduction , 2005, Diabetologia.

[30]  S. Beske,et al.  Weight loss increases cardiovagal baroreflex function in obese young and older men. , 2005, American journal of physiology. Endocrinology and metabolism.

[31]  J. Born,et al.  Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings. , 2005, Metabolism: clinical and experimental.

[32]  E. Ford.  Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. , 2005, Diabetes care.

[33]  G. Mancia,et al.  Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome , 2005, Diabetologia.

[34]  S. Fowler,et al.  The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial , 2005, Annals of Internal Medicine.

[35]  G. Mancia,et al.  Effect of central and peripheral body fat distribution on sympathetic and baroreflex function in obese normotensives , 2004, Journal of hypertension.

[36]  A. F. Mackintosh,et al.  Sympathetic Neural Activation in Nondiabetic Metabolic Syndrome and Its Further Augmentation by Hypertension , 2004, Hypertension.

[37]  Jan Born,et al.  Intranasal insulin reduces body fat in men but not in women. , 2004, Diabetes.

[38]  R. Brook,et al.  Attenuation of haemodynamic, metabolic and energy expenditure responses to isoproterenol in patients with hypertension , 2004, Journal of hypertension.

[39]  P. Gorelick,et al.  Chronic Management of Blood Pressure After Stroke , 2004, Hypertension.

[40]  S. M. Robinson,et al.  Triglycerides induce leptin resistance at the blood-brain barrier. , 2004, Diabetes.

[41]  K. Matthews,et al.  Interactions Between Autonomic Nervous System Activity and Endothelial Function: A Model for the Development of Cardiovascular Disease , 2004, Psychosomatic medicine.

[42]  J. Carvalheira,et al.  Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats , 2003, Diabetologia.

[43]  T. Ogihara,et al.  Serum Uric Acid and Plasma Norepinephrine Concentrations Predict Subsequent Weight Gain and Blood Pressure Elevation , 2003, Hypertension.

[44]  M. Rondon,et al.  Weight loss improves neurovascular and muscle metaboreflex control in obesity. , 2003, American journal of physiology. Heart and circulatory physiology.

[45]  M. Esler,et al.  Relation Between Cardiac Sympathetic Activity and Hypertensive Left Ventricular Hypertrophy , 2003, Circulation.

[46]  A. Folsom,et al.  Prospective Investigation of Autonomic Nervous System Function and the Development of Type 2 Diabetes: The Atherosclerosis Risk In Communities Study, 1987–1998 , 2003, Circulation.

[47]  J. Fagius,et al.  Sympathetic nerve activity in metabolic control--some basic concepts. , 2003, Acta physiologica Scandinavica.

[48]  T. Laitinen,et al.  Weight loss and weight maintenance, ambulatory blood pressure and cardiac autonomic tone in obese persons with the metabolic syndrome , 2003, Journal of hypertension.

[49]  S A Stansfeld,et al.  Adrenocortical, Autonomic, and Inflammatory Causes of the Metabolic Syndrome: Nested Case-Control Study , 2002, Circulation.

[50]  S. Beske,et al.  Sympathetic Neural Activation in Visceral Obesity , 2002, Circulation.

[51]  K. Flegal,et al.  Prevalence and trends in obesity among US adults, 1999-2000. , 2002, JAMA.

[52]  G. Mancia,et al.  Short- and Long-Term Neuroadrenergic Effects of Moderate Dietary Sodium Restriction in Essential Hypertension , 2002, Circulation.

[53]  Jan Born,et al.  Sniffing neuropeptides: a transnasal approach to the human brain , 2002, Nature Neuroscience.

[54]  S. Beske,et al.  Reduced cardiovagal baroreflex gain in visceral obesity: implications for the metabolic syndrome. , 2002, American journal of physiology. Heart and circulatory physiology.

[55]  G. Mancia,et al.  Participation of the Hypothalamus-Hypophysis Axis in the Sympathetic Activation of Human Obesity , 2001, Hypertension.

[56]  H. Hirao,et al.  Calorie Restriction Reduced Blood Pressure in Obesity Hypertensives by Improvement of Autonomic Nerve Activity and Insulin Sensitivity , 2001, Journal of cardiovascular pharmacology.

[57]  J. Chan,et al.  Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese. , 2001, Metabolism: clinical and experimental.

[58]  T. Moritani,et al.  Comparison of thermogenic sympathetic response to food intake between obese and non-obese young women. , 2001, Obesity research.

[59]  M. Emdin,et al.  Hyperinsulinemia and Autonomic Nervous System Dysfunction in Obesity: Effects of Weight Loss , 2001, Circulation.

[60]  H. Yoshimatsu,et al.  VLCD-Induced Weight Loss Improves Heart Rate Variability in Moderately Obese Japanese , 2001, Experimental biology and medicine.

[61]  P. Björntorp,et al.  The activity of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system in relation to waist/hip circumference ratio in men. , 2000, Obesity research.

[62]  S. Woods,et al.  Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. , 2000, Diabetes.

[63]  H Ue,et al.  Autonomic responsiveness to acute cold exposure in obese and non-obese young women , 1999, International Journal of Obesity.

[64]  D. Seals,et al.  Neural mechanisms in human obesity-related hypertension. , 1999, Journal of hypertension.

[65]  S. Reynisdottir,et al.  Divergent effects of weight reduction and oral anticonception treatment on adrenergic lipolysis regulation in obese women with the polycystic ovary syndrome. , 1999, The Journal of clinical endocrinology and metabolism.

[66]  G. Grassi,et al.  How to assess sympathetic activity in humans. , 1999, Journal of hypertension.

[67]  M. Matsuda,et al.  Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. , 1999, Diabetes care.

[68]  K. Karason,et al.  Heart rate variability in obesity and the effect of weight loss. , 1999, The American journal of cardiology.

[69]  J. Hartikainen,et al.  The effect of a very low-calorie diet-induced weight loss on the severity of obstructive sleep apnoea and autonomic nervous function in obese patients with obstructive sleep apnoea syndrome. , 1998, Clinical physiology.

[70]  S. Woods,et al.  Obesity, diabetes and the central nervous system , 1998, Diabetologia.

[71]  G. Mancia,et al.  Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans. , 1998, Circulation.

[72]  G. Jennings,et al.  Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects. , 1997, Circulation.

[73]  L. Howes,et al.  Effects of dietary lipid modification on adrenoceptor-mediated cardiovascular responsiveness and baroreflex sensitivity in normotensive subjects. , 1997, Blood pressure.

[74]  S. Kahn,et al.  Insulin Transport From Plasma Into the Central Nervous System Is Inhibited by Dexamethasone in Dogs , 1996, Diabetes.

[75]  S. Rössner,et al.  Effects of weight reduction on the regulation of lipolysis in adipocytes of women with upper-body obesity. , 1995, Clinical science.

[76]  W. Saris,et al.  β-Adrenergically mediated thermogenic and heart rate responses: Effect of obesity and weight loss , 1995 .

[77]  I. Macdonald,et al.  The effects of weight loss in obese subjects on the thermogenic, metabolic and haemodynamic responses to the glucose clamp. , 1994, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[78]  G A McPherson,et al.  Heart Rate Spectral Analysis, Cardiac Norepinephrine Spillover, and Muscle Sympathetic Nerve Activity During Human Sympathetic Nervous Activation and Failure , 1994, Circulation.

[79]  P. Vollenweider,et al.  Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. , 1994, The Journal of clinical investigation.

[80]  E. Ravussin,et al.  Muscle Sympathetic Nerve Activity in Response to Glucose Ingestion: Impact of Plasma Insulin and Body Fat , 1994, Diabetes.

[81]  S. Julius,et al.  Reflex sympathetic activation induces acute insulin resistance in the human forearm. , 1993, Hypertension.

[82]  Y. Schutz,et al.  Postprandial thermogenesis in obese children before and after weight reduction. , 1992, European journal of clinical nutrition.

[83]  G. Hunter,et al.  Effect of weight reduction on resting energy expenditure, substrate utilization, and the thermic effect of food in moderately obese women. , 1992, The American journal of clinical nutrition.

[84]  Mikael Elam,et al.  Effect of Energy-Restricted Diet on Sympathetic Muscle Nerve Activity in Obese Women , 1991, Hypertension.

[85]  I. Meredith,et al.  Exercise Training Lowers Resting Renal But Not Cardiac Sympathetic Activity in Humans , 1991, Hypertension.

[86]  D. Porte,et al.  Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic Zucker rats , 1990, Peptides.

[87]  J. Saul,et al.  Heart rate and muscle sympathetic nerve variability during reflex changes of autonomic activity. , 1990, The American journal of physiology.

[88]  A. Astrup,et al.  Impaired glucose-induced thermogenesis and arterial norepinephrine response persist after weight reduction in obese humans. , 1990, The American journal of clinical nutrition.

[89]  J. Wahren,et al.  Meal-induced thermogenesis in obese patients before and after weight reduction. , 1989, Clinical physiology.

[90]  S. Woods,et al.  Reduced effect of experimental peripheral hyperinsulinemia to elevate cerebrospinal fluid insulin concentrations of obese Zucker rats. , 1987, Endocrinology.

[91]  B. Fagerberg,et al.  Reactivity to norepinephrine and effect of sodium on blood pressure during weight loss. , 1985, Hypertension.

[92]  P. Nestel,et al.  Blunted norepinephrine responsiveness to changing energy states in obese subjects. , 1985, Metabolism: clinical and experimental.

[93]  L. Landsberg,et al.  Impaired suppression of sympathetic activity during fasting in the gold thioglucose-treated mouse. , 1980, The Journal of clinical investigation.

[94]  J. Mariani,et al.  Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome. , 2009, The American journal of clinical nutrition.

[95]  P. Arner,et al.  Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation , 2007, International Journal of Obesity.

[96]  G. Eisenhofer.  Sympathetic nerve function--assessment by radioisotope dilution analysis. , 2005, Clinical autonomic research : official journal of the Clinical Autonomic Research Society.

[97]  M. Kunesova,et al.  In vivo increase in beta-adrenergic lipolytic response in subcutaneous adipose tissue of obese subjects submitted to a hypocaloric diet. , 1997, The Journal of clinical endocrinology and metabolism.

[98]  A. Mark,et al.  Mechanisms of insulin action on sympathetic nerve activity. , 1995, Clinical and experimental hypertension.

[99]  R. Schwartz,et al.  The effect of diet or exercise on plasma norepinephrine kinetics in moderately obese young men. , 1990, International journal of obesity.

[100]  J. Saul,et al.  Modulation of cardiac autonomic activity during and immediately after exercise. , 1989, The American journal of physiology.