Effects of PYY_1–36and PYY_3–36on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects

Abstract

Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. produced reduced EI, lower ratings of well-being, increases in FFA, postprandial glucose (only 0.8 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 PYY3-36) and insulin concentrations, as well as heart rate and EE (only 0.8 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 PYY3-36). PYY1-36 at 1.6 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 produced increased heart rate and postprandial insulin response. Ratings of appetite were opposite with infusions of 0.8 and 1.6 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 PYY1-36 and seemed to depend on subjects being lean or obese. PYY3-36 caused increased thermogenesis, lipolysis, postprandial insulin and glucose responses, suggestive of increased sympathoadrenal activity. PYY1-36 had no effect on EI and no clear effects on appetite but resulted in increased heart rate and postprandial insulin response. However, highest tolerable dose of PYY1-36 was probably not reached in the present study. Peptide YY; free fatty acids; insulin sensitivity; arcuate nucleus; neuropeptide Y receptors THE IMBALANCE BETWEEN energy intake (EI) and energy expenditure (EE) that produces the obese state may partly be a consequence of an inadequate appetite regulation. Hence, scientific interest in recent years has concentrated on both the secretion and function of different gastrointestinal hormones, and on the appetite regulatory centers of the brain, including the arcuate nucleus which is considered a key brain area (22).Peptide YY (PYY) is a 36-amino acid peptide released postprandially from the endocrine L cells in the distal gastrointestinal tract in proportion to the calorie and fat content of the ingested meal (1,8,18). PYY is part of the neuropeptide Y (NPY) protein family and exists in human blood in two forms: the intact PYY , in which the NH 2 -terminal Tyr-Pro dipeptide has been removed by dipeptidyl aminopeptidase IV (DPP IV) cleavage (12, 13). PYY 1-36 binds to and activates the Y1, Y2, and Y5 NPY receptor subtypes, whereas PYY 3-36 preferentially binds to the inhibitory presynaptic Y2 receptor, which is highly expressed in NPY neurons in the appetite regulatory center in the arcuate nucleus (27).Infusion of PYY 3-36 at doses producing supraphysiological plasma concentrations has been shown to result in a dosedependent decrease in subsequent food intake (8, 18). The highest suppression of food intake has been demonstrated with doses of 0.8 pmol⅐kg Ϫ1 ⅐min Ϫ1 and amounted to a decrease of between 25 and 34%, with the highest reduction in lean subjects (4,5,8,18) and a somewhat lower reduction in obese subjects (4). The differences in EI were observed either during the subsequent ad libitum meal or during the first 12 h after the infusion. In the context of appetite-suppressant effect in humans, the quantitative effect of PYY is of a magnitude not previously reported in connection with anorectic drugs (sibutramine etc.), and PYY receptors therefore constitute a very promising drug target for obesi...

Individually timing high-protein preloads has no effect on daily energy intake, peptide YY and glucagon-like peptide-1

“…In fact, the lowest infusion rate that elicited these changes in appetite and EI produced GLP-1 concentrations of 50 pmol/l (Flint et al, 1998) and changes in peptide YY of approximately 424% (Batterham et al, 2002). Some results (Sloth et al, 2007) actually suggest that circulating amounts of peptide YY3-36 need to increase three-to four-fold increase over values observed after nutrient stimulation only (Degen et al, 2005;le Roux et al, 2006b), to exert significant effects on EI. Furthermore, after surgery increases of both peptides YY and GLP-1 on nutrient stimulation have been shown to be approximately three times greater than that observed in control subjects (Korner et al, 2006(Korner et al, , 2007.…”

Therapy for Obesity Based on Gastrointestinal Hormones

“…Unfortunately, adverse effects like nausea and vomiting are very common. In a recent study by Sloth et al only 4 out of the first 9 participants succeeded in completing the high dose PYY(3-36) infusion (0.8 pmol/kg/min) due to the effects of nausea, vomiting, stomach pain, and flushing [77]. Thus, the dose of PYY(3-36) had to be decreased markedly.…”

“…In humans, intravenous infusion of PYY(3-36) reduces food intake in both lean and obese subjects [77]. Unfortunately, adverse effects like nausea and vomiting are very common.…”

Adult-onset PYY overexpression in mice reduces food intake and increases lipogenic capacity

“…Based on the differential effects of Y1 and Y2 signalling on energy and glucose homeostasis, and considering that PYY1-36 and PYY3-36 co-exist in the circulation in varying ratios depending on nutritional status (Grandt et al, 1994), PYY1-36 and PYY3-36 may act in a co-ordinate or synergistic manner to regulate energy and glucose metabolism in fasted and postprandial states. Investigating the physiological actions of total PYY on energy balance and glucose homeostasis is important for the development of PYY-based anti-obesity and anti-diabetes therapies, particularly considering that nausea and vomiting are common side-effects associated with PYY3-36 treatment (Degen et al, 2005, Gantz et al, 2007, Sloth et al, 2007and le Roux et al, 2008.…”