Wulff Birgitte S, Kuhre Rune Ehrenreich, Selvaraj Madhan, Rehfeld Jens F, Niss Kristoffer, Fels Johannes J, Anna Secher, Raun Kirsten, Gerstenberg Marina Kjaergaard
Global Drug Discovery, Novo Nordisk A/S, 2760, Måløv, Denmark.
Translational Research, Global Translation, Novo Nordisk A/S, 2760 Måløv, Denmark.
Heliyon. 2024 Jun 3;10(12):e32009. doi: 10.1016/j.heliyon.2024.e32009. eCollection 2024 Jun 30.
Co-treatment with long acting PYY and the GLP-1 receptor agonists has potential as an efficient obesity treatment. This study investigates whether the mechanisms behind additive reduction of food intake and weight loss depends on complementary effects in brain areas regulating food intake and if restoration of leptin sensitivity is involved.
Diet-induced obese (DIO) mice were co-treated with PYY(3-36) and exendin-4 (Ex4, GLP-1R agonist) for 14 days using minipumps. Leptin responsiveness was evaluated by measuring food intake and body weight after leptin injection, and gene expression profile was investigated in various of brain regions and liver.
We show that weight loss associated with co-treatment of PYY(3-36) and Ex4 and Ex4 mono-treatment in DIO mice increased expression of several genes in area postrema (AP) known to be involved in appetite regulation and and were synergistically upregulated by the co-treatment. The upregulations were independent of weight loss, as shown by inclusion of a weight matched control. Moreover, PYY(3-36) and Ex4 co-treatment resulted in synergistically upregulated plasma concentrations of soluble leptin receptor (SLR) and improved sensitivity to exogenous leptin demonstrated by food intake lowering.
The study results suggest that synergistic upregulation of appetite-regulating genes in AP and improved leptin sensitivity are important mediators for the additive weight loss resulting from PYY and Ex4 co-treatment.
长效PYY与胰高血糖素样肽-1（GLP-1）受体激动剂联合治疗有潜力成为一种有效的肥胖治疗方法。本研究调查食物摄入量额外减少和体重减轻背后的机制是否取决于调节食物摄入的脑区中的互补作用，以及是否涉及瘦素敏感性的恢复。
使用微型泵对饮食诱导肥胖（DIO）小鼠联合给予PYY（3-36）和艾塞那肽-4（Ex4，一种GLP-1受体激动剂），持续14天。通过注射瘦素后测量食物摄入量和体重来评估瘦素反应性，并研究不同脑区和肝脏中的基因表达谱。
我们发现，DIO小鼠中PYY（3-36）与Ex4联合治疗以及Ex4单药治疗导致的体重减轻增加了最后区（AP）中几个已知参与食欲调节的基因的表达，并且联合治疗使这些基因协同上调。如纳入体重匹配的对照组所示，这种上调与体重减轻无关。此外，PYY（3-36）与Ex4联合治疗导致可溶性瘦素受体（SLR）的血浆浓度协同上调，并通过降低食物摄入量证明对外源性瘦素有更高的敏感性。
研究结果表明，AP中食欲调节基因的协同上调和瘦素敏感性的改善是PYY与Ex4联合治疗导致额外体重减轻的重要介导因素。
