Targeting the Gut in Obesity: Signals from the Inner Surface

Natalia Petersen; Thomas U Greiner; Lola Torz; Angie Bookout; Marina Kjærgaard Gerstenberg; Carlos M Castorena; Rune Ehrenreich Kuhre

doi:10.3390/metabo12010039

Targeting the Gut in Obesity: Signals from the Inner Surface

Metabolites. 2022 Jan 5;12(1):39. doi: 10.3390/metabo12010039.

Authors

Natalia Petersen¹, Thomas U Greiner², Lola Torz^{1

3}, Angie Bookout⁴, Marina Kjærgaard Gerstenberg¹, Carlos M Castorena⁴, Rune Ehrenreich Kuhre^{1

3}

Affiliations

¹ Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Novo Park 1, 2670 Måløv, Denmark.
² The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
³ Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁴ Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk Research Center, Seattle, WA 98109, USA.

Abstract

Obesity is caused by prolonged energy surplus. Current anti-obesity medications are mostly centralized around the energy input part of the energy balance equation by increasing satiety and reducing appetite. Our gastrointestinal tract is a key organ for regulation of food intake and supplies a tremendous number of circulating signals that modulate the activity of appetite-regulating areas of the brain by either direct interaction or through the vagus nerve. Intestinally derived messengers are manifold and include absorbed nutrients, microbial metabolites, gut hormones and other enterokines, collectively comprising a fine-tuned signalling system to the brain. After a meal, nutrients directly interact with appetite-inhibiting areas of the brain and induce satiety. However, overall feeding behaviour also depends on secretion of gut hormones produced by highly specialized and sensitive enteroendocrine cells. Moreover, circulating microbial metabolites and their interactions with enteroendocrine cells further contribute to the regulation of feeding patterns. Current therapies exploiting the appetite-regulating properties of the gut are based on chemically modified versions of the gut hormone, glucagon-like peptide-1 (GLP-1) or on inhibitors of the primary GLP-1 inactivating enzyme, dipeptidyl peptidase-4 (DPP-4). The effectiveness of these approaches shows that that the gut is a promising target for therapeutic interventions to achieve significant weigh loss. We believe that increasing understanding of the functionality of the intestinal epithelium and new delivery systems will help develop selective and safe gut-based therapeutic strategies for improved obesity treatment in the future. Here, we provide an overview of the major homeostatic appetite-regulating signals generated by the intestinal epithelial cells and how these signals may be harnessed to treat obesity by pharmacological means.

Keywords: appetite regulation; enteroendocrine cells; enterokines; gut microbiota; intestinal remodelling; nutrient metabolism; therapeutic potential.

Publication types

Review