Diet-induced obesity (DIO) and adult onset diabetes (AODM), which are reaching epidemic proportions in industrialized nations, may be considered as aberrant physiological responses induced by recent lifestyle alterations in genetically predisposed individuals. Intestinal parasitic nematode infections, which have a significant effect on the nutritional status of the host, in general, and on glucose utilization, in particular, provide a link between nutrition and the immune response. We now provide evidence that mouse strains that are prone to DIO and AODM are also susceptible to chronic infection, whereas mice strains that have a lean phenotype are resistant to nematode infections. In Preliminary Data, we show that two genes of the RELM/FIZZ family, known as resistin and RELMbeta, play an important role in glucose metabolism and resistance to intestinal parasitic nematode infections, respectively. RELMbeta expression can be induced in lean/resistant strains of mice, whereas resistin protein is most highly expressed in obese/susceptible strains. We also show that the adipokine, leptin, augments the expression of RELMbeta during Th2-mediated immune stimulation, supporting the premise that leptin is a critical link between DIO, metabolism, and the inflammatory response to parasitic infections. We therefore hypothesize that leptin regulates both the metabolic response and the immune-activated expression of RELMbeta, allowing effective adaptation of the host to parasitic nematode infections of the intestinal tract. Through the study of intestinal nematode infections, measurements of immunologic and metabolic parameters, studies of RELMbeta gene regulation, and the examination of RELMbeta-/- and resistin-/- mice, we propose to use RELMbeta and resistin as models to elucidate leptin-dependent and -independent differences in the host response that are genetically determined in inbred strains of mice. These studies will provide novel insights into the mechanisms by which nutrition affects metabolic and immunologic responses to intestinal parasitic infections.
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