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  • Research Summary of John E. Hall, PhD

    Regulation of Appetite and Metabolism in Obesity;
    Mechanisms of Obesity Hypertension and Target Organ Injury

    Background

    Our previous experimental and theoretical studies suggest that abnormalities of kidney function, manifest by impaired pressure natriuresis, underlie all forms of hypertension studied thus far. In some cases, these disturbances originate intrarenally, but often they occur via activation of neurohumoral mechanisms that impair renal excretory capability. Therefore, a large share of our research has been directed toward understanding the intrarenal and neurohumoral mechanisms that regulate kidney function, and how they are altered in pathophysiologic conditions such as hypertension.

    Obesity is a primary cause of human essential hypertension.

    During the past several years, we have studied extensively obesity hypertension, which may have special relevance to human essential hypertension. Currently, 30-35% of the adult population in the United States is overweight, with a body mass index (BMI) greater than about 27 kg/m2. In certain populations, such as elderly African-American women, the prevalence of obesity may be as high as 70-80%, similar to their prevalence of hypertension. Population studies have clearly documented the relationship between obesity and hypertension; hypertension usually occurs in populations that have an increase in body weight with aging, but is rare when body weight does not increase with aging. Also, 75-85% of essential hypertensive subjects are overweight, an observation that is consistent with the hypothesis that excess weight gain is responsible, in large part, for the high prevalence of essential hypertension in industrialized societies. However, the factors that link excess weight gain with hypertension are still unknown.

    Obesity is a major risk factor for cardiac, vascular, and kidney disease.

    Considerable evidence indicates that even modest overweight is an independent predictor of vascular disease, stroke, congestive heart failure, and cardiovascular death. Obesity may also be a major cause of end-stage renal disease (ESRD). According to the United States Renal Data Systems Survey, the two leading causes of ESRD are diabetes and hypertension. At least 80-90% of diabetics are type II (non-insulin dependent diabetics (NIDDM), who are almost invariably overweight. Moreover, the majority of hypertensive patients are overweight, and there is evidence that excess weight is a major cause of human essential hypertension. These considerations suggest that obesity may also be one of the most important causes of ESRD. However, the mechanisms that link obesity with cardiovascular and renal injury are poorly understood.

    Current research

    Central nervous system regulation of blood pressure and Mmetabolism in obesity

    We have previously shown that activation of the sympathetic nervous system (SNS), via the renal nerves, and intrarenal structural changes play a major role in the pathophysiology of obesity hypertension. We also found that leptin, a cytokine released from adipocytes, contributes to SNS activation and increased blood pressure (BP) mainly by stimulating the central nervous system (CNS) Pro-opiomelanocortin (POMC) pathway and ultimately by activation of melanocortin 4 receptors (MC4R). However, the CNS circuits and cell signaling mechanisms that mediate the chronic effects of the leptin-melanocortin system on renal symp[athetic nerve activity (RSNA), BP, and metabolism are poorly understood.

    A central hypothesis of our current research is that leptin-melanocortin activation in distinct areas of the brain and through multiple intracellular signaling pathways can differentially and independently regulate appetite, energy expenditure, RSNA and BP. (Figure 1). The overall goal of our studies is therefore to determine the CNS signaling mechanisms that mediate the chronic effects of leptin-melanocortin activation on RSNA, BP, and metabolism, including food intake, oxygen consumption (VO2) and energy expenditure, and the specific areas of the brain that are most important in differentially controlling these cardiovascular and metabolic effects of the CNS leptin-melanocortin system.

    The specific aims of this research are:

    1) To determine the role of leptin receptors (LR) in the forebrain, POMC and paraventricular (PVN) neurons in constitutive regulation of metabolic and cardiovascular function and in mediating chronic actions of leptin on control of appetite, VO2 and energy expenditure, RSNA and BP.

    2) To determine the specific roles of Stat3, Shp2-MAPK, and Irs2-PI3K signaling in the forebrain, POMC and PVN neurons in constitutive regulation of metabolic and cardiovascular function and in mediating chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin.

    3) To determine the role of MC4R activation in the forebrain and PVN neurons in controlling metabolic and cardiovascular functions and in mediating chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin.

    These studies employ novel, genetically engineered mouse models in which the LR or specific leptin signaling pathways are conditionally deleted in the forebrain, POMC or PVN neurons or in the entire brain using the Cre/LoxP recombinase system to determine the brain regions and cell signaling mechanisms that mediate the chronic divergent actions of leptin on BP, RSNA, and metabolic functions including appetite, VO2 and energy expenditure, and glucose regulation.

    The role of the POMC-MC4R in specific CNS regions in mediating the chronic actions of leptin will be determined in mice with mutated MC4R (loxTB-MC4R-/- mice) where the MC4R is "rescued" in the forebrain, or PVN neurons, or the entire brain by specific expression of Cre-recombinase in these areas. Integrative physiological methods, including 24 hrs/day monitoring of BP, RSNA, kidney function, and metabolic functions, in combination with novel genetic models provide a unique and powerful approach to determining the complex CNS circuits and signaling pathways by which the leptin-melanocortin systems regulate BP, RSNA and metabolic functions that determine energy balance.

    These experiments will provide a comprehensive analysis of key brain signaling mechanisms that link control of cardiovascular and metabolic functions, including appetite, VO2 and energy expenditure. The use of these novel mouse models in combination with sophisticated methods for measuring integrative cardiovascular and metabolic functions will provide important new insights into fundamental mechanisms of energy homeostasis as well as obesity-associated SNS activation and hypertension.

    Mechanisms of obesity-induced target organ injury

    Established risk factors such as increased blood pressure, cardiac hypertrophy, diabetes clearly play an important role in linking obesity to cardiac and renal dysfunction and eventually heart failure and kidney disease. Obesity markedly increases the workload on the heart, with high cardiac output as well as high blood pressure, and could unmask latent ventricular dysfunction of other etiologies. Obesity also causes increased intrarenal pressures and other accumulation of extracellular matrix that could be the precursors of renal injury associated with chronic obesity. The renin-angiotensin-aldosterone system and SNS are activated in obesity and increased activity of these systems has been implicated in the pathophysiology of chronic heart failure and renal disease.

    Lipid accumulation in and around myocytes or in the kidneys may also contribute to cardiac and renal cell death and eventually cardiomyopathy and renal disease. Although adipocytes have the capacity to store large amounts of excess free fatty acids in cytosolic lipid droplets, cells of non-adipose tissues such as the heart and kidneys have a limited capacity for storage of lipids. When this capacity is exceeded, the excess lipid may lead to cell dysfunction or cell death. Although studies in obese rodents suggest that cardiac and renal steatosis (lipid accumulation) can lead to lipotoxic injury of these tissues, the cellular mechanisms involved await further investigation.

    Recent studies suggest that increased leptin, a hormone released from adipocytes, may protect against lipid accumulation in non-adipocyte tissues such as the heart, kidneys and liver, by stimulating β-oxidation of fatty acids. This stimulatory effect on β-oxidation shunts fatty acids from away from storage, thus, reducing lipid accumulation.

    Role of mitochondrial dysfunction and endoplasmic reticulum stress in obesity-induced renal injury and protective role of leptin

    The central hypothesis of these studies is that obesity promotes renal lipid accumulation and thereby stimulates mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which lead to renal injury (Figure 2).

    Our experiments also will test the hypothesis that increased levels of leptin protect against renal lipid accumulation, mitochondrial dysfunction and ER stress in obesity, whereas increased angiotensin II promotes renal lipotoxicity. We utilize unique, genetically engineered animal models of obesity and a combination of physiological, pharmacological, and molecular approaches to test our hypothesis. The specific aims of these studies are to answer the following questions:

    1) Does obesity cause mitochondrial dysfunction and ER stress, which promote renal injury?

    2) Does leptin protect against renal lipid accumulation, mitochondrial dysfunction, ER stress, and renal injury in obesity by stimulating β-oxidation of fatty acids?

    3) Does increased angiotensin II induce renal mitochondrial dysfunction and ER stress and contribute to renal lipid accumulation and renal injury in obesity?

    Further reading

    • do Carmo JM, da Silva AA, Cai Z, Dubinion JH, Hall JE. Control of arterial pressure, appetite and glucose by leptin in mice lacking leptin receptors in POMC neurons. Hypertension 2011; 57: Mar 21. [Epub ahead of print].
    • Dubinion JH, da Silva AA, Hall JE. Chronic blood pressure and appetite responses to central leptin infusion in rats fed a high fat diet. J Hypertension 2011; 29: 758-762.
    • do Carmo JM, Bassi M, da Silva AA, Rushing J, Hall JE. Systemic but not central nervous system nitric oxide synthase inhibition exacerbates the hypertensive effect of chronic melanocorin 3/4 receptor activation. Hypertension 2011; 57: 428-434.
    • Hall JE, daSilva AA, doCarmo JM, Dubinion J, Hamza S, Munusamy S, Smith G, Stec D. Obesity-induced hypertension: role of sympathetic nervous system, leptin and melanocortins. J Biol Chem 2010; 285: 17271-17276.
    • Dubinion J, daSilva AA, Hall JE. Enhanced blood pressure and appetite responses to chronic central melanocortin 3/4 receptor blockade in dietary-induced obesity. J Hypertension 2010; 28:1466-1470.
    • daSilva AA, do Carmo JM, Freeman JN, Tallam LS, Hall JE. A functional melanocortin system is required for CNS mediated chronic antidiabetic and cardiovascular actions of leptin. Diabetes 2009; 58:1749-1756.
    • do Carmo JM, Tallam LS, Roberts JV, Brandon EL, Biglane J, daSilva AA, Hall JE. Impact of obesity on renal structure and function in the presence and absence of hypertension: Evidence from melanocortin 4-receptor deficient mice. Am J Physiol Regul Integr Comp Physiol. 2009; 297: R803-R812.
    • do Carmo, J.M., J.E. Hall, A.A. da Silva. Chronic central leptin infusion restores cardiac sympathetic-vagal balance and baroreflex sensitivity in diabetic rats. Am J Physiol Heart Circ Physiol. 295: H1974-1981, 2008.
    • Hall, J.E., A. A. da Silva, E. Brandon, D.E. Stec, Z.Ying, and D.W. Jones. Pathophysiology of obesity hypertension and target organ injury. In: Comprehensive Hypertension. Eds. Lip, G.Y.P. and J.E. Hall. Elsevier, New York, N.Y., 2007. pp. 447-468.
    • da Silva, A.A., J.M. do Carmo, B. Kanyicska, J. Dubinion, E. Brandon, and J.E. Hall. Endogenous melanocortin activity contributes to the elevated arterial pressure in spontaneously hypertensive rats. Hypertension 51:884-890, 2008.
    • Tallam, L.S., A. A. da Silva, and J. E. Hall. The melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin. Hypertension 48: 58-64, 2006.
    • Davy, K.P. and J.E. Hall. Obesity and hypertension: two epidemics or one? Am. J. Physiol. 286: R803-R813, 2004.
    • Hall, J.E., J.R. Henegar, T.M. Dwyer, J. Liu, A.A. da Silva, J.J. Kuo, and L. Tallam. Is obesity a major cause of chronic renal disease? Advances in Renal Replacement Therapy 11: 41-54, 2004.