Interactions between glucagon like peptide 1 (GLP-1) and estrogens regulates lipid metabolism

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2024-11-13 DOI:10.1016/j.bcp.2024.116623

Jorge F.A. Model , Rafaella S. Normann , Éverton L. Vogt , Maiza Von Dentz , Marjoriane de Amaral , Rui Xu , Tsvetan Bachvaroff , Poli Mara Spritzer , J. Sook Chung , Anapaula S. Vinagre

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Abstract

Obesity, characterized by excessive fat accumulation in white adipose tissue (WAT), is linked to numerous health issues, including insulin resistance (IR), and type 2 diabetes mellitus (DM2). The distribution of adipose tissue differs by sex, with men typically exhibiting android adiposity and pre-menopausal women displaying gynecoid adiposity. After menopause, women have an increased risk of developing android-type obesity, IR, and DM2. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are important in treating obesity and DM2 by regulating insulin secretion, impacting glucose and lipid metabolism. GLP-1Rs are found in various tissues including the pancreas, brain, and adipose tissue. Studies suggest GLP-1RAs and estrogen replacement therapies have similar effects on tissues like the liver, central nervous system, and WAT, probably by converging pathways involving protein kinases.

To investigate these interactions, female rats underwent ovariectomy (OVR) to promote a state of estrogen deficiency. After 20 days, the rats were euthanized and the tissues were incubated with 10 μM of liraglutide, a GLP-1RA. Results showed significant changes in metabolic parameters: OVR increased lipid catabolism in perirenal WAT and basal lipolysis in subcutaneous WAT, while liraglutide treatment enhanced stimulated lipolysis in subcutaneous WAT. Liver responses included increased stimulated lipolysis with liraglutide. Transcriptome analysis revealed distinct gene expression patterns in WAT of OVR rats and those treated with GLP-1RA, highlighting pathways related to lipid and glucose metabolism. Functional enrichment analysis showed estrogen’s pivotal role in these pathways, influencing genes involved in lipid metabolism regulation.

Overall, the study underscores GLP-1RA acting directly on adipose tissues and highlights the complex interactions between GLP-1 and estrogen in regulating metabolism, suggesting potential synergistic therapeutic effects in treating metabolic disorders like obesity and DM2.

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胰高血糖素样肽 1（GLP-1）与雌激素之间的相互作用可调节脂质代谢。

肥胖症的特征是白色脂肪组织（WAT）中脂肪堆积过多，它与许多健康问题有关，包括胰岛素抵抗（IR）和 2 型糖尿病（DM2）。脂肪组织的分布因性别而异，男性通常表现为甲状腺肥大，绝经前女性则表现为妇科类肥胖。绝经后，女性患雌激素型肥胖、IR 和 DM2 的风险增加。胰高血糖素样肽 1（GLP-1）受体激动剂（GLP-1RAs）通过调节胰岛素分泌、影响葡萄糖和脂质代谢，对治疗肥胖症和 DM2 具有重要作用。GLP-1Rs 存在于多种组织中，包括胰腺、大脑和脂肪组织。研究表明，GLP-1RAs 和雌激素替代疗法对肝脏、中枢神经系统和脂肪组织等组织有类似的影响，可能是通过涉及蛋白激酶的汇合途径来实现的。为了研究这些相互作用，雌性大鼠接受了卵巢切除术（OVR），以促进雌激素缺乏状态。20 天后，对大鼠实施安乐死，并用 10 μM 的利拉鲁肽（一种 GLP-1RA 药物）培养大鼠组织。结果显示，代谢参数发生了明显变化：OVR增加了肾周WAT的脂质分解和皮下WAT的基础脂肪分解，而利拉鲁肽治疗则增强了皮下WAT的刺激性脂肪分解。肝脏的反应包括利拉鲁肽刺激性脂肪分解的增加。转录组分析显示，OVR大鼠和接受GLP-1RA治疗的大鼠脂肪中的基因表达模式截然不同，突出了与脂质和葡萄糖代谢相关的通路。功能富集分析表明，雌激素在这些通路中起着关键作用，影响着参与脂质代谢调节的基因。总之，该研究强调了 GLP-1RA 直接作用于脂肪组织，并突出了 GLP-1 和雌激素在调节新陈代谢方面复杂的相互作用，这表明在治疗肥胖和 DM2 等代谢性疾病方面具有潜在的协同治疗效果。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.