The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery

Brandon Boland, Cardiovascular, Renal & Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, USA. bolandb@MedImmune.com.
Michael B. Mumphrey, Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. mumphrey@umich.edu.
Zheng Hao, Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. haozhg@outlook.com.
Benji Gill, Cardiovascular, Renal & Metabolic Diseases, MedImmune, Gaithersburg, MD 20878, USA. Gillb@MedImmune.com.
R Leigh Townsend, Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. townserl@pbrc.edu.
Sangho Yu, Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. sangho.yu@pbrc.edu.
Heike Münzberg, Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. heike.munzberg@pbrc.edu.
Christopher D. Morrison, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Maria G. Montez, Division of Nephrology, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Stephanie T. Broyles, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, USA.
Martha Walker, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Gina Evans-Hudsnall, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

Document Type

Article

Publication Date

3-10-2019

Abstract

BACKGROUND/GOALS: The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight. METHODS: Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype (WT) mice made obese on high-fat diet. RESULTS: Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, insulin resistance (HOMA-IR), and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice. CONCLUSIONS: PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as glucagon-like peptide-1 (GLP-1) remain to be investigated.

Publication Source (Journal or Book title)

Nutrients

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