Glucagon-like peptide-1 (GLP-1) is encoded by the preproglucagon gene (Gcg) and expressed in the intestine, pancreas, and central nervous system (CNS). Activation of GLP-1 receptors (GLP-1R) on pancreatic alpha-cells induces insulin secretion in a glucose-dependent manner while activation of CNS GLP-1Rs suppress feeding. Thus, Gcg-derived peptides play an important role in gluco- and body weight regulation, and GLP-1 has been implicated in the success of bariatric surgery. GLP-1 agonists are an effective treatment of type 2 diabetes mellitus (T2DM) and obesity. The predominant source of circulating GLP-1 is the intestine, but the alpha-cell becomes an important source when the islet is metabolically stressed. Further, plasma GLP-1 is increased in T2DM patients in response to inflammation. Nutrient-stimulated GLP-1 functions as an incretin, however, the function of GLP-1 during inflammation is unknown. My dissertation proposes that during inflammation, GLP-1 plays a metabolic role, functioning to regulate glucose levels and food intake, and an immunologic role, functioning to regulate inflammation. I examined the metabolic and immunologic role of Gcg under inflammatory conditions. Using a combination of high-fat diet (HFD)-induced obesity and a mouse model of tissue-specific Gcg expression, I explored the function of GLP-1 in response to inflammation by administering lipopolysaccharide (LPS), a well-established tool for inducing inflammation. LPS is a known anorectic agent that also alters glucose homeostasis; both functions of GLP-1. I hypothesized that HFD would exacerbate physiological responses to LPS including increased plasma GLP-1, decreased blood glucose levels, and increased sickness-induced anorexia, as well as systemic inflammatory responses including increased plasma cytokines. Indeed, HFD did increase plasma pro-inflammatory cytokines, and GLP-1 levels in response to LPS and this was associated with greater anorexia in HFD-fed animals. In the next set of studies, I tested whether GLP-1 secreted from either the pancreas or intestine was directly regulating feeding and glucose responses to LPS. I hypothesized that increases in circulating GLP-1, primarily from the pancreas, were necessary for feeding and glucose responses to LPS. I found that while both pancreatic and intestinal Gcg contribute to circulating levels of GLP-1 after LPS, the availability of either source of GLP-1 had no impact on glucoregulatory or feeding responses. Because pancreatic GLP-1 is the more novel contributor to circulation, I investigated the impact of Gcg on pancreatic inflammation. I found that 24h after LPS, whole-body chow-fed Gcg Null animals had increased macrophage accumulation in the pancreas. I saw a similar trend in HFD-fed Gcg Null mice. Using a GLP-1R reporter mouse, I found that macrophages isolated from the pancreas, but not the bone marrow, express GLP-1R. These data suggest that pancreatic GLP-1 directly regulates local macrophage responses to inflammation. I conclude that under severe inflammatory conditions, GLP-1 plays an immunologic rather than metabolic role in the pancreatic responses to LPS, through direct macrophage regulation. This dissertation indicates a new role for GLP-1 signaling to pancreatic macrophages in response to inflammation. Future studies will explore the impact of this increased macrophage accumulation on long-term pancreatic function. In fact, my preliminary data demonstrate that IP glucose tolerance was impaired 2 weeks following LPS. This lasting impact of inflammation on pancreatic function points to a new use of GLP-1 agonists to protect pancreatic tissue during severe inflammation such as sepsis, or more recently, COVID-19.PHDNutritional SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/169674/1/emdavi_1.pd
