GLP-1 and energy balance: an integrated model of short-term and long-term control

Abstract

Glucagon-like peptide 1 (GLP-1), a peptide secreted from the intestine in response to nutrient ingestion, is perhaps best known for its effect on glucose-stimulated insulin secretion. GLP-1 is also secreted from neurons in the caudal brainstem, and it is well-established that, in rodents, central administration of GLP-1 potently reduces food intake. Over the past decade, GLP-1 has emerged not only as an essential component of the system that regulates blood glucose levels but also as a viable therapeutic target for the treatment of type 2 diabetes mellitus. However, although GLP-1 receptor agonists are known to produce modest but statistically significant weight loss in patients with diabetes mellitus, our knowledge of how endogenous GLP-1 regulates food intake and body weight remains limited. The purpose of this Review is to discuss the evolution of our understanding of how endogenous GLP-1 modulates energy balance. Specifically, we consider contributions of both central and peripheral GLP-1 and propose an integrated model of short-term and long-term control of energy balance. Finally, we discuss this model with respect to current GLP-1-based therapies and suggest ongoing research in order to maximize the effectiveness of GLP-1-based treatment of obesity.

Insulin-like peptide 5 is an orexigenic gastrointestinal hormone

“…The nodose ganglion also expresses receptors for GLP-1, PYY and CCK, supporting the established view that the afferent vagus nerve contributes to the anorexigenic actions of a number of endogenous hormones released locally within the intestinal epithelium (19,20). Acting on the intrinsic enteric plexus, Insl5, like several other metabolically relevant gut hormones, may contribute to the coordination of colon motility and secretion, ensuring the efficient mixing, fermentation and propulsion of ingesta.…”

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2)

“…To avoid hyperinsulinemia, secreted insulin would induce CEACAM1 phosphorylation to promote receptor-mediated insulin uptake (34) and hepatic insulin clearance (9, 10) to maintain normal insulin metabolism and action on glucose homeostasis. Given that GLP-1 prompts transition into the fasting state (35), this may also constitute a negative feedback mechanism to ultimately recover CEACAM2 levels and limit insulin secretion. Of note, CEACAM2 is expressed in the kidney but not liver (4,29).…”

Hypothalamo-gastrointestinal axis – role in food intake regulation

“…Also in healthy and obese humans, the intravenous administration of GLP-1 reduces food intake in a dose dependent manner (Verdich et al, 2001). The results of studies on rodents have revealed that the effect of GLP-1 on the suppression of appetite is abolished by vagotomy which suggests that GLP-1 can act vagal and brainstem pathways (Abbott et al, 2005;Barrera et al, 2011).…”