Liraglutide + PYY3-36 Combination Therapy Mimics Effects of Roux-en-Y Bypass on Early NAFLD Whilst Lacking-Behind in Metabolic Improvements

Abstract

Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY3-36) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY3-36 (0.1 mg/kg/day), liraglutide+PYY3-36, and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY3-36 induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY3-36- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY3-36 partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.

A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

“…Results of a study published by Dischinger, Hasinger et al (2020) support this concept. Specifically, while obesity surgery and LIRA/PYY3-36 co-administration resulted in comparable changes in body weight in obese rats, only surgery resulted in profound changes to the hypothalamic transcriptome; these findings may explain in part the limited nature of the metabolic improvements observed in response to pharmacologic intervention (Dischinger, Hasinger et al 2020, Metzner, Herzog et al 2022. Others have demonstrated that the positive outcomes of obesity surgery (i.e., changes in body weight and improved glucose homeostasis) are sustained in mice in the absence of GLP-1R or Y2-R, or both GLP-1R and Y2-R (Ye, Hao et al 2014).…”

“…These drugs also have similar shortcomings when used to treat obesity alone (Borner, Tinsley et al 2022). In response to these concerns, several novel dual or triple agonists have been created based on the structures of gut hormone agonists that are complementary to GLP-1, including glucagon, glucosedependent insulinotropic polypeptide (GIP), and peptide YY3-36 (PYY3-36) (Talsania, Anini et al 2005, Chepurny, Bonaccorso et al 2018, Frias, Nauck et al 2018, Kjaergaard, Salinas et al 2019, Milliken, Elfers et al 2021, Ostergaard, Paulsson et al 2021, Battelino, Bergenstal et al 2022, Boland, Laker et al 2022, Heise, Mari et al 2022, Jastreboff, Aronne et al 2022, Metzner, Herzog et al 2022, Zhao, Yan et al 2022). PYY1-36 is a gut hormone that binds to the Y1-R in pancreatic islets and central nervous system (CNS) nuclei that control appetite regulation in the brain including the brainstem area postrema (AP) and nucleus tractus solitarius (NTS), where it has an anorectic effect (Walther, Morl et al 2011).…”

“…PYY 3–36 , a truncated peptide agonist derived from dipeptidyl peptidase IV (DPPIV)-mediated proteolysis of full-length PYY 1–36 , is of particular interest as it binds preferentially to the anorectic neuropeptide Y2-R (Talsania, Anini et al 2005, Kjaergaard, Salinas et al 2019, Merkel, Moreno et al 2021, Ostergaard, Paulsson et al 2021, Metzner, Herzog et al 2022). PYY 3-36 crosses the blood-brain-barrier (Nonaka, Shioda et al 2003) and inhibits food intake via its interactions with Y2-R in brain areas that regulate energy homeostasis, including the ARC of the hypothalamus and the AP and NTS of the hindbrain (Shaw, Gackenheimer et al 2003, Fetissov, Byrne et al 2004, Neary, Small et al 2005, Blevins, Chelikani et al 2008).…”

“…Recent work suggested that the reduction in both food intake and body weight observed in response to combined treatment with GLP-1RAs and PYY 3-36 results in synergistically-enhanced activation of discrete hypothalamic and brainstem circuits that regulate appetite, including the arcuate nucleus (ARC), the paraventricular nuclei of the hypothalamus (PVNs), the central nucleus of the amygdala (CeA), and the hindbrain (AP/NTS) (Dischinger, Corteville et al 2019, Kjaergaard, Salinas et al 2019, Lafferty, Flatt et al 2021, Metzner, Herzog et al 2022). Combination therapy has also resulted in improved glucoregulation via an increase in insulin sensitivity, an observation that has been linked to the recovery of pancreatic β-cell function (Lafferty, Flatt et al 2021).…”

Hypertension Related to Obesity: Pathogenesis, Characteristics and Factors for Control

“…PYY3-26 agonists are subsequently being developed and tested as anti-obesity agents. In a rat model, Roux-en-Y gastric bypass (RYGB) and liraglutide+PYY 3-36 induced a similar body weight loss, however only RYGB induced significant metabolic improvements [ 210 ]. PYY does not appear to have a direct role in the treatment of hypertension but might promise a reduction in blood pressure through its anti-obesity effects.…”