Obesity is an independent risk factor for type 2 diabetes mellitus, cardiovascular disease, non-alcoholic steatohepatitis, stroke and certain cancers. A critical factor in obesity disorders is adipose tissue (AT) inflammation, which is caused in large part by macrophages that infiltrate AT. Neither the precipitating event(s) nor function(s) of macrophage infiltration into AT are known. Our data demonstrate that >90% of macrophages in AT of obese mice and humans are localized to sites of adipocyte death, where they surround and scavenge remnant lipid droplets and express cytokines (TNF-alpha, IL-6) that can dysregulate adipocyte insulin signaling, PPAR-gamma-dependent gene expression and lipolysis. Notably, adipocyte death increases dramatically with obesity and is temporally correlated with the onset and development of insulin resistance in mice. These data suggest a model of obesity-associated AT inflammation in which obesity promotes adipocyte death, adipocyte death recruits and activates macrophages, and macrophage-derived pro-inflammatory mediators promote additional adipocyte death and inflammation. Studies will test this model in mice, using morphological, and cell biological gene expression and metabolic approaches.
In Aim 1 we will use a transgenic mouse model of caspase 8-induced adipocyte apoptosis to determine the contribution of adipocyte death to AT inflammation and insulin resistance in the presence and absence of obesity-related factors.
In Aim 2 we use a knockout mouse that is deficient in macrophage inflammatory (NF-?B) dependent gene expression to determine the contribution of macrophage pro-inflammatory mediators to adipocyte dysregulation and death.
In Aim 3 we use transgenic mouse models of adipocyte hypertrophy and hyperplasia, respectively to test the hypothesis that obesity-associated adipocyte death and macrophage infiltration of AT occur preferentially in AT depots that expand primarily by hypertrophy (i.e., epididymal).
|Bennett, Grace; Strissel, Katherine J; DeFuria, Jason et al. (2014) Deletion of TNF-like weak inducer of apoptosis (TWEAK) protects mice from adipose and systemic impacts of severe obesity. Obesity (Silver Spring) 22:1485-94|
|Canaan, Allon; DeFuria, Jason; Perelman, Eddie et al. (2014) Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. Proc Natl Acad Sci U S A 111:5313-8|
|Denis, Gerald V; Obin, Martin S (2013) 'Metabolically healthy obesity': origins and implications. Mol Aspects Med 34:59-70|
|Vieira Potter, Victoria J; Strissel, Katherine J; Xie, Chen et al. (2012) Adipose tissue inflammation and reduced insulin sensitivity in ovariectomized mice occurs in the absence of increased adiposity. Endocrinology 153:4266-77|
|Perfield 2nd, James W; Lee, Yunkyoung; Shulman, Gerald I et al. (2011) Tumor progression locus 2 (TPL2) regulates obesity-associated inflammation and insulin resistance. Diabetes 60:1168-76|
|Greenberg, Andrew S; Coleman, Rosalind A; Kraemer, Fredric B et al. (2011) The role of lipid droplets in metabolic disease in rodents and humans. J Clin Invest 121:2102-10|
|Shaul, Merav E; Bennett, Grace; Strissel, Katherine J et al. (2010) Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet--induced obesity in mice. Diabetes 59:1171-81|
|Rogers, Nicole H; Perfield 2nd, James W; Strissel, Katherine J et al. (2010) Loss of ovarian function in mice results in abrogated skeletal muscle PPARdelta and FoxO1-mediated gene expression. Biochem Biophys Res Commun 392:1-3|
|Strissel, Katherine J; DeFuria, Jason; Shaul, Merav E et al. (2010) T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring) 18:1918-25|
|Rogers, Nicole H; Perfield 2nd, James W; Strissel, Katherine J et al. (2009) Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology 150:2161-8|