Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

Abstract

■ AbstractIt is estimated that 347 million people worldwide have diabetes and that over 1.5 billion adults worldwide are overweight. Predictions suggest these rates are increasing. Diabetes is a common complication in overweight and obese subjects, and in 2004, an estimated 3.4 million people died from consequences of high blood sugar. Thus, there is great interest in revealing the physiological systems that regulate body weight and blood sugar. Several peptidergic systems within the central nervous system and the periphery regulate energy homeostasis. A number of these systems have been investigated as potential treatments for obesity and the metabolic syndrome. However, manipulation of peptidergic systems poses many problems. This review discusses the peptidergic systems currently attracting research interest for their clinical potential to treat obesity. We consider first neuropeptides in the brain, including the orexigenic neuropeptide Y and melanin-concentrating hormone, and anorectic factors such as the melanocortins, ciliary neurotrophic factor, and neuromedin U. We subsequently discuss the utility of targeting peripheral gut peptides, including pancreatic polypeptide, peptide YY, amylin, and the gastric hormone ghrelin. Also, we analyze the evidence that these factors or drugs based on them may be therapeutically useful, while considering the disadvantages of using such peptides in a clinical context.

The modulatory role of high fat feeding on gastrointestinal signals in obesity

“…However, prolonged GLP-1 receptor antagonism attenuated these effects, reasserting the fact that blunted gut peptide signaling results in perpetuating weight gain and adiposity. Indeed, satiety is decreased in obese individuals [127], and more specifically following a HF meal [145], and impairments in several of the GI peptides have been associated with pathogenesis of obesity [146][147][148].…”

Small lipidated anti-obesity compounds derived from neuromedin U

“…Considering current trends in obesity/diabetes treatment [55], the development of long-acting analogs of NmU is highly desirable. Such analogs could be used in combination therapies with, for example, incretin-based therapeutic(s) such as semaglutide [56–58], a long-acting glucagon-like peptide 1 (GLP-1) analog that possesses a plasma half-life of 160 h. Since NM4A showed limited activity in a once-weekly regimen we synthesized double-lipidated analogs that should theoretically have improved pharmacokinetic properties.…”

Regulation of Appetite, Body Composition, and Metabolic Hormones by Vasoactive Intestinal Polypeptide (VIP)

“…Recently, several neuromediators have been suggested to play an important role in the regulation of appetite/satiety, feeding behavior and also in energy balance and metabolism (Wang, 2007; Greenwood, 2011; Vu, 2011). The ARC neurons, containing neurotransmitter peptides associated with appetite signals (Woods, 1998), communicate with each other and with higher brain centers through released PACAP, neuropeptide Y, agouti-related peptide neurons and melanocortin-releasing neurons (Delgado, 1996; Barsh, 2000).…”

“…The gastrointestinal tract (GI) acts as a nutrient sensor in response to luminal stimuli, releasing gastrointestinal neurotransmitters and hormones (Woods, 1998; Dockray, 2004) which are considered to be the major peripheral regulators of appetite and satiety (Greenwood, 2011). Neuropeptides regulate important gastrointestinal functions such as motility, secretion, absorption and also they provide feedback to the central nervous system (CNS) to regulate appetite and feeding behavior.…”