The increased prevalence of obesity has increased the incidence of metabolic syndrome. Metabolic syndrome associated disorders include non-insulin dependent diabetes mellitus (NIDDM), non-alcoholic fatty liver disease, hypertension, and heart disease. Genetic or diet-induced obesity in the C57BL/6J mouse is a frequently employed model of metabolic syndrome. Yet, despite an increase in adiposity, the melanocortin 3 receptor (MC3-R) -/- C57BL/6J mouse exhibits a dramatic attenuation of the symptoms of metabolic syndrome. Preliminary evidence suggests that a defect in non-esterified fatty acid (NEFA) mobilization, despite normal adrenergic sensitivity, may serve to protect the obese MC3-R -/- mouse from metabolic syndrome. I propose to 1) determine the role of adrenergic tone in adipocyte hypertrophy and metabolism in the MC3-R -/- mouse, 2) identify alternative metabolic fuels compensating for decreased NEFA availability in the energy restricted MC3-R -/- mouse, and 3) determine if decreased NEFA release in the MC3-R -/- mouse attenuates metabolic syndrome.
The first aim will include a rigorous determination of MC3-R and MC4-R effects on sympathetic tone in white adipose tissue (WAT), as a mechanism behind the reduced NEFA release. This set of experiments is encouraged by reports that MC3/4-R co-stimulation increases WAT sympathetic tone (Brito et al. 2007;Nogueiras et al. 2007).
Aim 1 will examine sensitivity to ip injected ^-agonists and antagonists, identify basal norepinephrine (NE) and NE turnover in WAT of WT, MC4-R -/-, and MC3-R -/- mice, and identify the role pharmacological blockade and stimulation of central MC3-R on WAT basal NE and NE turnover. Mobilized fatty acids serve to meet the energy requirements of the animal during times of dietary insufficiency. An inability to mobilize fatty acids during metabolic stress, requires use of alternative metabolic fuels, data in the MC3-R -/- mouse suggests that increased protein metabolism may meet metabolic requirements. Therefore, aim 2 will focus on fast-induced protein metabolism in wild-type (WT) and MC3-R -/- mice. To address the final aim, we will assess metabolic syndrome associated immune markers after inducing NEFA mobilization in the MC3-R -/- mouse. Furthermore, we will prevent fatty acid mobilization in the DIO mouse and examine the severity of metabolic syndrome. Results from these studies will identify the role of MC3-R on fatty acid mobilization and skeletal muscle turnover, as well as evaluate the role of altered fatty acid mobilization on the attenuated metabolic syndrome of the MC3-R -/- mouse. These findings will help evaluate the viability of pharmacological MC3-R manipulation as a treatment to decrease obesity associated complications.
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