Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Japan.
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Japan.
Peptides. 2018 Dec;110:10-18. doi: 10.1016/j.peptides.2018.10.006. Epub 2018 Oct 29.
There is a marked increase in the incidence of visceral adiposity and insulin resistance among women following menopause. Adrenomedullin (AM) is an endogenous peptide first identified as a vasodilator, but now known to exert a variety of physiological effects. RAMP3 is a receptor activity-modifying protein that binds to the AM receptor (calcitonin receptor-like receptor). As expression of both AM and RAMP3 is reportedly activated by estrogen, we hypothesized that RAMP3 is crucially involved in the pathophysiology of postmenopausal obesity. To test this idea, we compared the effects of ovariectomy (OVX) and a high-fat diet for 10 weeks (a model of postmenopausal obesity) between RAMP3 knockout (RAMP3-/-) and wild-type mice. RAMP3-/- OVX mice exhibited greater obesity and adipose tissue weight gain as compared to wild-type OVX mice. RAMP3-/- OVX mice also exhibited higher serum insulin levels. In periuterine WAT from RAMP3-/- OVX mice, expression of lipolysis-related factors was lower and expression of inflammation-related factors was higher than in wild-type OVX mice. Hepatic steatosis was also exacerbated in RAMP3-/- OVX. Notably, expression of the membrane-type estrogen receptor GPR30 was downregulated in periuterine WAT from RAMP3-/- OVX mice. These findings raise the possibility that a GPR30-RAMP3 interaction is involved in the pathophysiology of postmenopausal obesity and suggest RAMP3 plays a key role in the regulation of energy metabolism and exerts a hepatoprotective effect in this model of postmenopausal obesity. RAMP3 may thus be a useful therapeutic target for treatment of postmenopausal obesity and metabolic disorders.
绝经后女性内脏脂肪增多和胰岛素抵抗的发生率明显增加。肾上腺髓质素（AM）是一种内源性肽，最初被鉴定为血管扩张剂，但现在已知具有多种生理作用。RAMP3 是一种受体活性修饰蛋白，可与 AM 受体（降钙素受体样受体）结合。由于 AM 和 RAMP3 的表达据称均受雌激素激活，我们假设 RAMP3 是绝经后肥胖症病理生理学的关键因素。为了验证这一观点，我们比较了 RAMP3 敲除（RAMP3-/-）和野生型小鼠的卵巢切除术（OVX）和 10 周高脂肪饮食（绝经后肥胖模型）的影响。与野生型 OVX 小鼠相比，RAMP3-/-OVX 小鼠表现出更大的肥胖和脂肪组织重量增加。RAMP3-/-OVX 小鼠的血清胰岛素水平也更高。在 RAMP3-/-OVX 小鼠的periuterine WAT 中，与脂肪分解相关的因子表达较低，与炎症相关的因子表达较高，而野生型 OVX 小鼠则较低。RAMP3-/-OVX 小鼠的肝脂肪变性也加剧。值得注意的是，RAMP3-/-OVX 小鼠的 periuterine WAT 中的膜型雌激素受体 GPR30 的表达下调。这些发现提出了一种可能性，即 GPR30-RAMP3 相互作用可能涉及绝经后肥胖症的病理生理学，并表明 RAMP3 在能量代谢的调节中发挥关键作用，并在这种绝经后肥胖模型中发挥肝保护作用。因此，RAMP3 可能是治疗绝经后肥胖和代谢紊乱的有用治疗靶点。
