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.

Figure 1

Model of GLP-1 physiology. Nutrient ingestion stimulates intestinal L-cell secretion of glucagon-like peptide 1 (GLP-1), which activates local GLP-1 receptors (GLP1R) to initiate afferent vagal neurotransmission to the hindbrain. These vagal afferent signals, combined with those initiated by gastric distension, may activate hindbrain GLP-1-producing neurons, which in turn activate hindbrain GLP1R, as well as other hindbrain neurons to produce efferent signals leading to decreased meal size. In addition, signaling from hindbrain GLP-1-producing neurons to hypothalamic targets promotes decreased fat mass.