Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden.
Faculty of Medicine, King Abdulaziz University and Hospital, Al Ehtifalat St., Jeddah 21589, Saudi Arabia.
Cells. 2022 Mar 11;11(6):970. doi: 10.3390/cells11060970.
The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the brain. Therefore, genetic and pharmacological studies were performed to identify how central regulates energy metabolism and feeding behavior. We found that inhibiting , in insulin-producing cells of the (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the induced hyperphagia phenotype requires a conserved insulin-regulated α-glucosidase, (). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.
他汀类药物的靶标 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）与体重指数（BMI）密切相关，但 HMGCR 如何影响 BMI 尚不清楚。在哺乳动物中，外周 HMGCR 的研究并未明确确定其在 BMI 维持中的作用，而且尽管中枢神经系统表达量相当大，但中枢 HMGCR 的功能尚未确定。与哺乳动物相似，Hmgcr 在大脑中高度表达。因此，进行了遗传和药理学研究，以确定中枢神经系统如何调节能量代谢和摄食行为。我们发现，抑制胰岛素产生细胞（PI）中的 HMGCR，即果蝇下丘脑的等效物，可显著降低胰岛素样肽的表达，严重降低胰岛素信号。事实上，在整个发育过程中降低 HMGCR 的表达会导致体重减轻、脂质储存增加、高血糖和多食。此外，诱导的多食表型需要保守的胰岛素调节的α-葡萄糖苷酶（Glc）。在大鼠和小鼠中，急性抑制下丘脑 Hmgcr 活性会刺激摄食。这项研究提供了证据，证明中枢神经系统 Hmgcr 对代谢和摄食的调节如何影响 BMI。
