Metabolic regulation of adipocyte-macrophage crosstalk in obesity Summary Obesity-associated adipose tissue inflammation critically contributes to the development of insulin resistance and type 2 diabetes. While much evidence demonstrates the importance of both adipocytes and macrophages in initiating adipose tissue inflammation, little is known about precisely how nutrient metabolism is linked to inflammatory responses in both adipocytes and macrophages. It is also unknown about the mechanisms underlying metabolic regulation of the crosstalk between adipocytes and macrophages. The long-term goal of this research is to dissect adipocyte-macrophage crosstalk so that novel evidence-based approaches can be developed for preventing and/or treating insulin resistance. As an adipose tissue-abundant gene, PFKFB3 encodes for a regulatory enzyme whose product stimulates glycolysis. For this project, the central hypothesis is that PFKFB3 orchestrates appropriate metabolic regulation of adipocyte-macrophage crosstalk to suppress macrophage proinflammatory (M1) activation, stimulate macrophage alternative (M2) activation, and improve adipocyte functions, thereby protecting against obesity-associated adipose tissue inflammation and systemic insulin resistance. This hypothesis is based on the following novel findings: 1) PFKFB3 stimulates adipocyte production of palmitoleate (a mono-unsaturated fatty acid), which in turn blunts macrophage M1 activation;2) PFKFB3 is involved in PPARgamma stimulation of macrophage M2 activation;and 3) Myeloid cell-specific PFKFB3 disruption exacerbates diet-induced adipose tissue dysfunctions. Thus, the goal of this project is to define the novel role of PFKFB3 in regulating adipocyte-macrophage crosstalk. Accordingly, mice with selective PFKFB3 disruption in adipocytes and/or myeloid cells are generated.
For Specific Aim 1, experiments have been designed to test the hypothesis that adipocyte factors generated in response to PFKFB3 action, in particular palmitoleate, suppress macrophage M1 activation and/or stimulate macrophage M2 activation. Moreover, the in vivo effects of adipocyte PFKFB3 disruption on adipose tissue macrophage polarization, adipose tissue inflammation, and systemic insulin sensitivity will be examined.
For Specific Aim 2, experiments have been designed to test the hypothesis that PFKFB3 links nutrient metabolism and macrophage polarization. Also, the in vivo effects of PFKFB3 disruption in myeloid cells on adipose tissue inflammation and systemic insulin sensitivity will be examined.
For Specific Aim 3, experiments have been designed to test the hypothesis that the PFKFB3 in adipocytes and/or macrophages is needed for actions of PPARgamma activation. Accordingly, the involvement of the PFKFB3 in adipocytes versus macrophages in PPARgamma regulation of adipocyte-macrophage crosstalk, adipose tissue inflammation, and systemic insulin sensitivity will be examined. Together, the proposed research will illustrate a new paradigm on metabolic regulation of adipocyte-macrophage crosstalk, and provide the experimental basis for insulin sensitization by means of selective PFKFB3 activation.
Results from the proposed research will significantly advance the knowledge of metabolic regulation of adipocyte-macrophage crosstalk in relation to systemic insulin sensitivity. Furthermore, the successful completion of this project will support the development of novel PFKFB3-based approaches, in addition to thiazolidinediones (PPARgamma agonists) as insulin-sensitizers, for preventing and/or treating insulin resistance and related diseases.
|Woo, Shih-Lung; Xu, Hang; Li, Honggui et al. (2014) Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLoS One 9:e91111|
|Xu, Hang; Li, Honggui; Woo, Shih-Lung et al. (2014) Myeloid cell-specific disruption of Period1 and Period2 exacerbates diet-induced inflammation and insulin resistance. J Biol Chem 289:16374-88|
|Xu, Yiming; An, Xiaofei; Guo, Xin et al. (2014) Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol 34:1231-9|