Inflammation Meets Metabolic Disease: Gut Feeling Mediated by GLP-1

Abstract

Chronic diseases, such as obesity and diabetes, cardiovascular, and inflammatory bowel diseases (IBD) share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways, such as the unfolded protein response (UPR), alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular, the L-cell-derived incretin hormone glucagon-like peptide 1 (GLP-1) has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D). Yet, accumulating data indicate a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment, including the microbiota via receptors and transporters. Subsequently, mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling. This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity, and disease.

Obesity in IBD: epidemiology, pathogenesis, disease course and treatment outcomes

“…Although current epidemiological data is unable to accurately assess the directionality of this association, preclinical data suggests that dysbiosis and altered metabolic gut signalling induced by IBD and acting through hormones (including incretins such as gastric inhibitory polypeptide and glucagon-like peptide), satiety-related peptides (such as ghrelin and peptide YY) and bile acids might contribute to development of obesity and dysmetabolism in patients with IBD 27,28 . In addition, smoking cessation and use of corticosteroids could contribute to weight gain in patients with IBD; in the general population, the average magnitude of weight gain with smoking cessation and corticosteroid use is 3–5 kg; ~11% of patients who quit smoking and ~24% of patients on corticosteroids for >1 year gain >10 kg body weight 29–31 .…”

Gastrointestinal Complications of Obesity

“…77 Given the contradictory data in these 2 studies, the significance of these adipokine levels still is unclear. Inflammatory disease affecting the ileocolonic mucosa also could impact the synthesis or release of incretins, which may have metabolic effects, 78 and, paradoxically, increased release of glucagon-like peptide-1 has been reported to retard gastric emptying in patients with active inflammatory bowel disease. 79 …”

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

“…58 Although glucose tolerance and the glucose-lowering effects of GLP-1 are not affected in mice lacking neuronal GLP1R, GLP-1R agonists have no effect on food intake and body weight, or causing a conditioned taste aversion in those mice. 59 Moreover, beneficial effects of GLP-1 independent of glucose homeostasis have been described in heart [60][61][62][63] , adipose tissue 64,65 , skeleton 66 , subpopulations of immune cells 67,68 , and other target organs, 69,70 through direct actions on tissues expressing GLP-1R and indirect effects mediated by neuronal and endocrine pathways. …”