PACAP and VIP Neuropeptides' and Receptors' Effects on Appetite, Satiety and Metabolism.

The overwhelming increase in the prevalence of obesity and related disorders in recent years is one of the greatest threats to the global healthcare system since it generates immense healthcare costs. As the prevalence of obesity approaches epidemic proportions, the importance of elucidating the mechanisms regulating appetite, satiety, body metabolism, energy balance and adiposity has garnered significant attention. Currently, gastrointestinal (GI) bariatric surgery remains the only approach capable of achieving successful weight loss. Appetite, satiety, feeding behavior, energy intake and expenditure are regulated by central and peripheral neurohormonal mechanisms that have not been fully elucidated yet. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Vasoactive Intestinal Polypeptide (VIP) are members of a family of regulatory peptides that are widely distributed in parallel with their specific receptors, VPAC1R, VPAC2R and PAC1R, in the central nervous system (CNS) and in the periphery, such as in the gastrointestinal tract and its associated organs and immune cells. PACAP and VIP have been reported to play an important role in the regulation of body phenotype, metabolism and homeostatic functions. The purpose of this review is to present recent data on the effects of PACAP, VIP, VPAC1R, VPAC2R and PAC1R on the modulation of appetite, satiety, metabolism, calorie intake and fat accumulation, to evaluate their potential use as therapeutic targets for the treatment of obesity and metabolic syndrome.

Cholesterol-lowering effects of dietary pomegranate extract and inulin in mice fed an obesogenic diet.

BACKGROUND: It has been demonstrated in animal studies that both polyphenol-rich pomegranate extract (PomX) and the polysaccharide inulin, ameliorate metabolic changes induced by a high-fat diet, but little is known about the specific mechanisms. OBJECTIVE: This study evaluated the effect of PomX (0.25%) and inulin (9%) alone or in combination on cholesterol and lipid metabolism in mice. METHODS: Male C57BL/6 J mice were fed high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose)] diets supplemented with PomX (0.25%) and inulin (9%) alone or in combination for 4 weeks. At the end of intervention, serum and hepatic cholesterol, triglyceride levels, hepatic gene expression of key regulators of cholesterol and lipid metabolism as well as fecal cholesterol and bile acid excretion were determined. RESULTS: Dietary supplementation of the HF/HS diet with PomX and inulin decreased hepatic and serum total cholesterol. Supplementation with PomX and inulin together resulted in lower hepatic and serum total cholesterol compared to individual treatments. Compared to HF/HS control, PomX increased gene expression of Cyp7a1 and Cyp7b1, key regulators of bile acid synthesis pathways. Inulin decreased gene expression of key regulators of cholesterol de novo synthesis Srebf2 and Hmgcr and significantly increased fecal elimination of total bile acids and neutral sterols. Only PomX in combination with inulin reduced liver and lipid weight significantly compared to the HF/HS control group. PomX showed a trend to decrease liver triglyceride (TG) levels, while inulin or PomX-inulin combination had no effect on either serum or liver TG levels. CONCLUSION: Dietary PomX and inulin supplementation decreased hepatic and serum total cholesterol by different mechanisms and the combination leading to a significant enhancement of the cholesterol-lowering effect.

Dietary pomegranate extract and inulin affect gut microbiome differentially in mice fed an obesogenic diet.

Growing evidence suggests that dysbiosis of gut microbiota is associated with pathogenesis of a variety of human diseases. Using dietary intervention to shape the composition and metabolism of the gut microbiota is increasingly recognized. In the present study, we investigated the effects of polysaccharide inulin and polyphenol-rich pomegranate extract (PomX) alone or in combination on the cecal microbiota composition and function in a diet induced obesity mouse model. Male C57BL/6 mice were randomly divided into four experimental groups and consumed either high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose, 17% energy from protein)] diet, HF/HS diet supplemented with PomX (0.25%), or inulin (9%) or PomX and inulin in combination for 4 weeks. In mice fed the PomX-diet the proportion of Turicibacteraceae and Ruminococcaceae was significantly increased compared to the control HF/HS diet. Supplementation with inulin alone and inulin + PomX combination significantly increased the proportion of Verrucomicrobiaceae (A. muciniphila) and decreased Clostridiaceae. Only mice fed the inulin diet experienced an increase in serum lipopolysaccharide (LPS) and monocyte chemoattractant protein 1 (MCP-1), which was reversed when feeding the inulin + PomX diet. Feeding the inulin + PomX diet was associated with a significant increase in Bifidobacteriaceae and Rikenellaceae, which may have contributed to the reduction of endotoxemia markers. Inulin supplementation showed lower species richness of gut microbiota compared to mice fed with HF/HS or HF/HS/PomX, and the reduction was reversed by the addition of PomX. Inulin alone and in combination with PomX had distinct microbial clusters determined by both weighted and unweighted UniFrac Beta-Diversity principle coordinate analysis. A total of 19 KEGG biological pathways were significantly regulated in the gut microbiota with PomX and inulin alone or combined treatment. Inulin significantly enhanced KEGG infectious disease-related pathway associated with increase of serum LPS and MCP-1. No changes in gene expression of ileal proinflammatory cytokine and tight junction genes were observed in mice treated with PomX and inulin. Our results demonstrated that the gut microbiota and their biological pathways were differentially effected by dietary PomX and inulin fed combined or alone. It is therefore very important to consider the interaction among bioactive components of food when evaluating potential prebiotic effects.