The prevalence of obesity and associated co-morbidities, including type 2 diabetes and cardiovascular disease (CVD), has increased dramatically in the past several decades. While weight loss is the ideal approach to reduce the negative metabolic consequences of obesity, it is clear that sustained weight loss is difficult to achieve. In fact, only 20% of people who lose at least 10% of their body weight are able to maintain that loss for greater than 2 years. These bouts of weight loss followed by subsequent weight gain lead to ?weight-cycling?. Interestingly, several studies in humans demonstrate that weight-cycling increases the risk of developing metabolic diseases. While the potentially deleterious effects of weight-cycling are recognized, the mechanisms by which weight- cycling increases metabolic dysfunction remain unknown. During the past decade, we have come to understand that the immune system plays a key role in the pathological consequences of obesity. Metabolic organs such as the liver, muscle, and adipose tissue (AT) accumulate immune cells that subsequently impact the insulin sensitivity of the parenchymal cells. In particular, obesity results in a dramatic increase in the number of inflammatory AT macrophages and AT T lymphocytes (ATTs). Interestingly, the accumulation of T cells in obese AT appears to be antigen-driven and is also characterized by the formation of memory cells. To determine if weight cycling alters immune responses in AT, we developed a mouse model of weight cycling using alternating high fat (HF) and low fat (LF) diet feeding. Similar to what is seen in humans; the weight-cycled mice had increased fasting glucose levels and impaired systemic glucose tolerance compared to mice that gained weight but did not cycle (weight-gain controls). Furthermore, AT-specific insulin signaling was abolished in the weight-cycled mice. At the end of the study, the macrophage populations in AT were unchanged in their number and phenotype. However, ATT number and the expression of multiple TH1-associated genes were significantly increased in the AT of the weight-cycled mice. These data demonstrate that weight cycling induces a potent T cell-driven adaptive immune response in the AT and suggest that weight cycling actually induce a secondary adaptive immune response. Thus, the overall hypothesis of this application is: weight-cycling results in an accelerated secondary adaptive immune response that heightens inflammation in AT, leading to local and systemic insulin resistance. This hypothesis will be tested in the following 3 aims: 1) To determine whether weight cycling alters ATT phenotype and function; 2) To determine if weight cycling induces secondary immune responses in AT; 3) To determine whether weight cycling modulates regulatory T cell (Treg) phenotype and function.

Public Health Relevance

Obesity has become a worldwide epidemic resulting in increased incidence of many different diseases. Recent evidence suggests that weight cycling is associated with elevated risk of diabetes and cardiovascular disease. As such, scientific discovery toward understanding the mechanisms by which weight cycling has adverse metabolic effects is of utmost importance.

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Cottam, Matthew A; Itani, Hana A; Beasley 4th, Arch A et al. (2018) Links between Immunologic Memory and Metabolic Cycling. J Immunol 200:3681-3689
Bolus, W Reid; Peterson, Kristin R; Hubler, Merla J et al. (2018) Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments. Mol Metab 8:86-95
McDonnell, Wyatt J; Koethe, John R; Mallal, Simon A et al. (2018) High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity. Diabetes 67:2361-2376
Peterson, Kristin R; Cottam, Matthew A; Kennedy, Arion J et al. (2018) Macrophage-Targeted Therapeutics for Metabolic Disease. Trends Pharmacol Sci 39:536-546
Peterson, Kristin R; Flaherty, David K; Hasty, Alyssa H (2017) Obesity Alters B Cell and Macrophage Populations in Brown Adipose Tissue. Obesity (Silver Spring) 25:1881-1884
Orr, Jeb S; Kennedy, Arion J; Hill, Andrea A et al. (2016) CC-chemokine receptor 7 (CCR7) deficiency alters adipose tissue leukocyte populations in mice. Physiol Rep 4:
Hill, Andrea A; Anderson-Baucum, Emily K; Kennedy, Arion J et al. (2015) Activation of NF-?B drives the enhanced survival of adipose tissue macrophages in an obesogenic environment. Mol Metab 4:665-77
Hubler, Merla J; Peterson, Kristin R; Hasty, Alyssa H (2015) Iron homeostasis: a new job for macrophages in adipose tissue? Trends Endocrinol Metab 26:101-9
Riley, Kimberly G; Pasek, Raymond C; Maulis, Matthew F et al. (2015) Macrophages are essential for CTGF-mediated adult ?-cell proliferation after injury. Mol Metab 4:584-91
Bolus, W Reid; Gutierrez, Dario A; Kennedy, Arion J et al. (2015) CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue. J Leukoc Biol 98:467-77