ABSTRACT
Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism. © 2020 American Physiological Society. Compr Physiol 10:99-124, 2020.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Gastrointestinal Hormones/agonists , Obesity/drug therapy , Peptides/agonists , Animals , Bariatric Surgery , Diabetes Mellitus, Type 2/metabolism , Gastrointestinal Hormones/metabolism , Humans , Obesity/metabolism , Obesity/surgery , Peptides/metabolismABSTRACT
Recently, we showed that double-transgenic rats overexpressing guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), specifically in macrophages demonstrate an antiobesity phenotype and low-expression levels of proinflammatory cytokines in the mesenteric fat even when fed a high-fat diet. Here, we examined the levels and mechanism of Gn and GC-C transcription following saturated fatty acid and lipopolysaccharide (LPS), an activator of Toll-like receptor 4 (TLR4), exposure by using the NR8383 macrophage cell line. In addition, the levels of guanylin and cGMP were increased by addition of either palmitic acid or LPS. Next, we investigated the interaction of the gene transcription and nuclear factor-κB (NF-κB) by using an NF-κB inhibitor and chromatin immunoprecipitation assay. We showed that palmitic acid induced Gn gene expression via TLR4 and NF-κB. Moreover, we demonstrated that NF-κB binding to the Gn promoter was responsible for the induction of gene transcription by palmitic acid or LPS. Our results indicate that saturated fatty acids such as palmitic acid activate Gn gene expression via the NF-κB pathway, raising the possibility that the activated Gn-GC-C system may contribute to the inhibition of high-fat diet-induced proinflammatory cytokines in macrophages.
Subject(s)
Gastrointestinal Hormones/genetics , Lipopolysaccharides/pharmacology , Macrophages, Alveolar/drug effects , NF-kappa B/genetics , Natriuretic Peptides/genetics , Palmitic Acid/pharmacology , Toll-Like Receptor 4/genetics , Animals , Cell Line , Cyclic GMP/immunology , Cyclic GMP/metabolism , Gastrointestinal Hormones/agonists , Gastrointestinal Hormones/immunology , Gene Expression Regulation , Genes, Reporter , Humans , Luciferases/genetics , Luciferases/metabolism , Macrophages, Alveolar/cytology , Macrophages, Alveolar/immunology , Mice , NF-kappa B/immunology , Natriuretic Peptides/agonists , Natriuretic Peptides/immunology , RAW 264.7 Cells , Rats , Receptors, Guanylate Cyclase-Coupled/genetics , Receptors, Guanylate Cyclase-Coupled/immunology , Signal Transduction , THP-1 Cells , Toll-Like Receptor 4/immunologyABSTRACT
Obesity and its comorbidities, such as type 2 diabetes, are pressing worldwide health concerns. Available anti-obesity treatments include weight loss pharmacotherapies and bariatric surgery. Whilst surgical interventions typically result in significant and sustained weight loss, available pharmacotherapies are far less effective, typically decreasing body weight by no more than 5-10%. An emerging class of multi-agonist drugs may eventually bridge this gap. This new class of specially tailored drugs hybridizes the amino acid sequences of key metabolic hormones into one single entity with enhanced potency and sustained action. Successful examples of this strategy include multi-agonist drugs targeting the receptors for glucagon-like peptide-1 (GLP-1), glucagon and the glucose-dependent insulinotropic polypeptide (GIP). Due to the simultaneous activity at several metabolically relevant receptors, these multi-agonists offer improved body weight loss and glucose tolerance relative to their constituent monotherapies. Further advancing this concept, chimeras were generated that covalently link nuclear acting hormones such as oestrogen, thyroid hormone (T3 ) or dexamethasone to peptide hormones such as GLP-1 or glucagon. The benefit of this strategy is to restrict the nuclear hormone action exclusively to cells expressing the peptide hormone receptor, thereby maximizing combinatorial metabolic efficacy of both drug constituents in the target cells whilst preventing the nuclear hormone cargo from entering and acting on cells devoid of the peptide hormone receptor, in which the nuclear hormone might have unwanted effects. Many of these multi-agonists are in preclinical and clinical development and may represent new and effective tools in the fight against obesity and its comorbidities.
Subject(s)
Gastrointestinal Hormones/agonists , Obesity/drug therapy , Peptides/therapeutic use , Animals , Gastrointestinal Hormones/physiology , Glucagon/agonists , Glucagon/physiology , Glucagon-Like Peptide 1/agonists , Glucagon-Like Peptide 1/physiology , Humans , Obesity/physiopathology , Peptides/pharmacologyABSTRACT
Bariatric surgery has proven to be an effective means of treating 'diabesity': the combination of type 2 diabetes mellitus (T2DM) and obesity. The effects of surgery go beyond weight loss but reflect a complex alteration in secretion of gut hormones. Finding a pharmaceutical alternative that mimics the benefits of surgery without surgical complications has become the 'holy grail' of the twenty-first century. As knowledge of the multifaceted functions of gut hormones increases, a multitude of drugs that exploit these actions has emerged. In this review, we examine the current understanding of the mechanisms by which bariatric surgery improves diabesity. We also discuss the rapidly emerging role of glucagon-like peptide-1-based treatments as well as the potential for new therapeutics based on other gut hormones (e.g. oxyntomodulin, peptide YY, gastric inhibitory peptide, ghrelin).
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Gastrointestinal Hormones/metabolism , Obesity/complications , Obesity/drug therapy , Receptors, Gastrointestinal Hormone/metabolism , Animals , Bariatric Surgery/adverse effects , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/surgery , Gastrointestinal Hormones/agonists , Gastrointestinal Hormones/antagonists & inhibitors , Ghrelin/antagonists & inhibitors , Ghrelin/metabolism , Humans , Molecular Targeted Therapy , Obesity/metabolism , Obesity/physiopathology , Obesity/surgery , Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/antagonists & inhibitors , Receptors, Ghrelin/antagonists & inhibitors , Receptors, Ghrelin/metabolismABSTRACT
Small mammalian proteins called the prokineticins [prokineticin 1 (PK1) and PK2] and two corresponding G-protein-coupled receptors [prokineticin receptor 1 (PKR1) and PKR2] have been identified recently, but the physiological role of the PK/PKR system remains mostly unexplored. Bv8, a protein extracted from frog skin, is a convenient and potent agonist for both PKR1 and PKR2, and injection of Bv8 in vivo causes a potent and long-lasting hyperalgesia. Here, we investigate the cellular basis of hyperalgesia caused by activation of PKRs. Bv8 caused increases in [Ca]i in a population of isolated dorsal root ganglion (DRG) neurons, which we identified as nociceptors, or sensors for painful stimuli, from their responses to capsaicin, bradykinin, mustard oil, or proteases. Bv8 enhanced the inward current carried by the heat and capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1) via a pathway involving activation of protein kinase Cepsilon (PKCepsilon), because Bv8 caused translocation of PKCepsilon to the neuronal membrane and because PKC antagonists reduced both the enhancement of current carried by TRPV1 and behavioral hyperalgesia in rodents. The neuronal population expressing PKRs consisted partly of small peptidergic neurons and partly of neurons expressing the N52 marker for myelinated fibers. Using single-cell reverse transcriptase-PCR, we found that mRNA for PKR1 was mainly expressed in small DRG neurons. Exposure to GDNF (glial cell line-derived neurotrophic factor) induced de novo expression of functional receptors for Bv8 in a nonpeptidergic population of neurons. These results show that prokineticin receptors are expressed in nociceptors and cause heat hyperalgesia by sensitizing TRPV1 through activation of PKCepsilon. The results suggest a role for prokineticins in physiological inflammation and hyperalgesia.
Subject(s)
Amphibian Proteins/pharmacology , Calcium/metabolism , Ganglia, Spinal/metabolism , Gastrointestinal Hormones/agonists , Membrane Potentials/physiology , Neurons/metabolism , Neuropeptides/pharmacology , TRPV Cation Channels/metabolism , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/agonists , Animals , Animals, Newborn , Cells, Cultured , Ganglia, Spinal/drug effects , Membrane Potentials/drug effects , Mice , Neurons/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
Many peptides are synthesised and released from the gastrointestinal tract. Whilst their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behaviour and thus potential anti obesity targets. Peptide YY (PYY) is released post prandially from the gastrointestinal L-cells with glucagon-like peptide 1 (GLP-1) and oxyntomodulin. Following peripheral administration of PYY 3-36, the circulating form of PYY, to mouse, rat or human there is marked inhibition of food intake. PYY 3-36 is thought to mediate its actions through the NPY Y2 GPCR. Obese subjects have lower basal fasting PYY levels and have a smaller post prandial rise. However, obesity does not appear to be associated with resistance to PYY (as it is with leptin) and exogenous infusion of PYY 3-36 results in a reduction in food intake by 30% in an obese group and 31% in a lean group. GLP-1 or oxyntomodulin, products of the prepreglucagon gene, decrease food intake when administered either peripherally or directly into the CNS. In addition, both have been shown to decrease food intake in humans. These effects are thought to be mediated by the GLP-1 receptor. Ghrelin, a huger hormone produced by the stomach, increases in the circulation following a period of fasting. Administration of ghrelin either peripherally or directly into the CNS increases food intake and chronic administration leads to obesity. Further infusion into normal healthy volunteers increases both food intake and appetite. Ghrelin is thought to act through the growth hormone secretagogue receptor (GHS-R). Obesity is the current major cause of premature death in the UK, killing almost 1000 people a week. Worldwide its prevalence is accelerating. The administration of the naturally occurring gut hormone may offer a long-term therapeutic approach to weight control. Here we consider the therapeutic potential of some gut hormones, and the GPCR's through which they act, in the treatment of obesity.