Daniel R. Kaiser, Ph.D.
Cardiovascular Division, University of Minnesota
Evidence is accumulating that obesity independently increases the risk for cardiovascular disease. The incidence of obesity is rising at alarming rates not only in adults, but also in children. Recent data indicates that childhood obesity predicts a broad range of adverse health effects in later adulthood and may increase the risk for future cardiovascular mortality. Cross-sectional studies show that obese, but otherwise healthy children have structural and functional abnormalities of the vasculature compared to normal weight peers.
In addition, obesity may increase systemic oxidative stress and inflammation thereby further contributing to vascular damage. In adults, exercise training is an effective means by which to improve vascular structure and function, and reduce systemic oxidative stress and inflammation in both healthy and diseased states. In a similar way, physical activity interventions in obese children and adolescents may serve to slow-down or possibly reverse the vascular abnormalities present in this population.
Pawel K. Olszewski, Ph.D.
Research Service, VA Medical Center, Minneapolis, MN
Ghrelin, a novel 28-amino acid peptide, acts as an endogenous ligand for the GH secretagogue receptor (GHS-R). Central and peripheral injections of this peptide stimulate feeding in rodents. Initial studies suggest that the lateral hypothalamus (LH), hypothalamic arcuate (ARC), and paraventricular (PVN) nuclei mediate orexigenic properties of ghrelin. Neurons synthesizing ghrelin are localized in the ARC, and the GHS-R exists in those three areas. A feeding response has been observed following administration of this substance into the PVN, ARC, and LH. Also, intracerebroventricular (ICV) injection of ghrelin induces Fos immunoreactivity (IR: Fos IR, a marker of neuronal activation) in the regions mentioned above.
Finally, preliminary evidence suggests that, within the LH-, PVN-, and ARC-derived circuitry, ghrelin interacts with orexin, Agouti-related protein (Agrp), NPY, and opioids. The current project focuses on understanding central mechanisms through which ghrelin affects consumption. The hypothesis is that ghrelin-induced hyperphagia is mediated by the LH, PVN, and ARC, and it stems from this peptide's interactions with other neuropeptidergic systems involved in feeding control.
Emphasis will be put on ghrelin's potential interactions with orexigenic peptides: opioids, Agrp, orexin and NPY. This project will also provide detailed characterization of ghrelin's effect on feeding, as its orexigenic properties have been primarily tested in chow-fed sated rats. Methods will include behavioral, microsurgical, and immunohistochemical techniques. Ghrelin and other peptides of interest will be delivered ICV or site specifically via a cannula. Activation of neurons and their biochemical nature will be defined using single and double immunostaining, including that for Fos.
Lincoln R. Potter, Ph.D.
Department of Biochemistry, Molecular Biology and Biophysics
University of Minnesota
The natriuretic peptide family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). ANP and BNP are cardiac hormones that antagonize the renin-angiotensin-aldosterone system and decrease blood pressure. CNP is a paracrine factor that stimulates vascular smooth muscle relaxation and long bone growth. Binding of these hormones is transduced into intracellular signals by natriuretic peptide receptor-A (NPR-A) and natriuretic peptide receptor-B (NPR-B), cell surface guanylyl cyclase receptors that catalyze the synthesis of the intracellular second messenger, cGMP. Recently, it was reported that ANP stimulates lipolysis in human adipocytes by a cGMP-dependent mechanism. This novel and unexpected observation suggests the existence of a previously unappreciated lipolytic pathway.
We propose to confirm these data in human adipocytes and determine whether a similar pathway exists in the well-characterized mouse 3T3 L1 fat cell line. In addition, we will extend these findings by determining whether cGMP-dependent protein kinases are required for this response using a combination of inhibitor and dominant-negative approaches. Finally, using the 3T3 L1 adipocytes, we will investigate the molecular basis of how isoproterenol and insulin sensitize and desensitize NPR-B, respectively. Together, these studies will advance our understanding of how cGMP stimulates lipid metabolism as well as how natriuretic peptide receptors are regulated in the fat cell environment.
Yourka Tchoukalova, M.D., Ph.D.
Endocrine Research Unit
Mayo Clinic, Rochester, MN
These studies are designed to assess the cellular characteristics of adipose tissue and preadipocyte physiology in the abdominal and femoral subcutaneous depots in upper body obesity and lower body obesity. Preliminary studies suggest that the cellularity of visceral adipose depots (considered more insulin resistant) is greater than abdominal subcutaneous (less insulin resistant) and that omental and mesenteric preadipocytes have altered rates of differentiation, proliferation, and apoptosis. These studies are to assess whether there is a similar relationship between subcutaneous abdominal fat tissue in upper body (more insulin resistant) obesity and subcutaneous abdominal fat tissue in lower body obesity (less insulin resistant) as well as between the femoral fat depots in both types of obesity.
Twenty women with upper body obesity and 20 women with lower body obesity will undergo measures of body composition (DEXA and abdominal CT), resting energy expenditure and have adipose tissue biopsies (abdominal subcutaneous and femoral subcutaneous). The number of different cell types, the rates of preadipocyte proliferation, differentiation, and apoptosis, and the regulation of key factors in these processes will be compared between sites and between groups to gain a better understanding for the processes of adipose tissue acquisition and insulin resistance development.
Chaodong Wu, Ph.D.
Department of Biochemistry, Molecular Biology and Biophysics
University of Minnesota
Obesity develops when energy intake exceeds energy expenditure over a considerable period of time. This positive energy balance is due to high energy intake or low energy expenditure, or a combination of these two factors. Regulation of energy balance is essential for the treatment of obesity. Decreasing food intake and/or increasing energy expenditure to regulate energy balance have been shown to reduce obesity. Particularly, acceleration of fatty acid oxidation in the liver is able to reduce obesity, or adiposity, in obese animal models. The enhanced fatty acid oxidation by transgenic modification of genes related to lipid biosynthesis, produced an increase in energy expenditure and improved glucose homeostasis.
To date, it remains unknown whether direct alteration of glucose and lipid metabolism can regulate energy balance through modulating metabolic pathways instead of by transgenic modification. Fructose-2,6-bisphosphate (F-2,6-P2) is a regulator that controls glucose metabolism in liver. Increasing hepatic F-2,6-P2 content via adenovirus-mediated overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF-2-K/F-2,6-P2ase) is able to reduce hepatic glucose output and decrease levels of circulating lipids in obese mice. Indeed, decreases in body weight and adiposity were observed in the obese mice when hepatic F-2,6-P2 was increased. Also, preliminary studies with mice having high F-2,6-P2 levels have shown only small decreases in food intake. However, the mechanisms for the reduction of adiposity in the obese mice are not clear. Based on the above observations, we hypothesize that increasing hepatic content of F-2,6-P2 will decrease adiposity mainly through increasing energy expenditure by accelerating lipid oxidation in the liver.
To test this hypothesis, we will study the effects of F-2,6-P2 on regulation of energy balance by carefully determining food intake and measuring carbon dioxide production and oxygen consumption using indirect calorimetry. By analyzing the ratio of carbon dioxide production to oxygen consumption, the respiratory quotient, the role of high F-2,6-P2 levels relative to accelerated lipid oxidation in increased energy expenditure will be addressed.
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