THE ROLE OF THE CXCL12/CXCR4 SIGNALING AXIS IN ADIPOCYTE BIOLOGY
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Mammalian adipose tissue can broadly be divided into two types of fat: brown adipose tissue (BAT) and white adipose tissue (WAT). While BAT is responsible for non-shivering thermogenesis via lipid metabolism, WAT stored fatty acids for long term energy use. However, BAT is primarily present in children and is all but lost by adulthood. Opposingly, WAT has the capacity to expand throughout life and contributes to negative health consequences. In BAT, sympathetic innervation drives adaptive thermogenesis, though molecular mechanisms contributing to BAT innervation are poorly understood. We have found that the administration of CXCL12 to mice causes an upregulation in BAT activity through sympathetic neuronal growth. Specifically, CXCL12 produced by smooth muscle cells is indirectly responsible for increased BAT presence and decreased BAT lipid accumulation, heightening thermogenic defense to cold stimuli. Here, CXCL12 is shown to retain CXCR4/CD301+ cells (M2 macrophages) within BAT, which directly influences sympathetic innervation of BAT, allowing for environmental stimulation for lipid-burning non-shivering thermogenesis. While CXCL12 influences BAT activation, the CXCL12/CXCR4 pathway plays a different role in WAT. Though body fat distribution is dictated by sex, molecular signaling governing adiposity remains elusive. Here, we identify that CXCL12/CXCR4 signaling is regulating adiposity in a sex-dependent manner. Deletion of CXCR4 in females, but not males, leads to a lipodystrophic phenotype and leads to an upregulation of estrogen receptor alpha, thus promoting estradiol sensitivity and blocking adipogenesis. Removal of estrogen restores WAT expansion in adipose lineage-specific CXCR4-deficient mice, highlighting the antiadipogenic role of estrogen in women. Overall, these studies suggest that the CXCL12/CXCR4 signaling axis is influencing maintenance and expansion of BAT and WAT. Targeting this pathway could pose a new therapy to combat metabolic dysregulation.
Adipocyte progenitor cells; Adipose tissue; Brown and beige fat; CXCL12/CXCR4 signaling; Estrogen; Sympathetic innervation
Kurpios, Natasza; Johnson, Elizabeth Lauren; Leak, Tashara Marie
Ph. D., Nutrition
Doctor of Philosophy
dissertation or thesis