Edison Biotechnology Institute, Ohio University, Athens, Ohio 45701, USA.
Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Athens, Ohio 45701, USA.
Endocrinology. 2022 Oct 1;163(10). doi: 10.1210/endocr/bqac129.
Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the effect that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity. To test the hypothesis that removal of GH action in adipocytes might partially replicate the increased lifespan and healthspan observed in global GHRKO mice, we assessed adiposity, cytokines/adipokines, glucose homeostasis, frailty, and lifespan in aging AdGHRKO mice of both sexes. Our results show that disrupting the GH receptor gene in adipocytes improved insulin sensitivity at advanced age and increased lifespan in male AdGHRKO mice. AdGHRKO mice also exhibited increased fat mass, reduced circulating levels of insulin, c-peptide, adiponectin, resistin, and improved frailty scores with increased grip strength at advanced ages. Comparison of published mean lifespan data from GHRKO mice to that from AdGHRKO and muscle-specific GHRKO mice suggests that approximately 23% of lifespan extension in male GHRKO is due to GHR disruption in adipocytes vs approximately 19% in muscle. Females benefited less from GHR disruption in these 2 tissues with approximately 19% and approximately 0%, respectively. These data indicate that removal of GH's action, even in a single tissue, is sufficient for observable health benefits that promote long-term health, reduce frailty, and increase longevity.
生长激素受体敲除 (GHRKO) 小鼠已被用于研究生长激素 (GH) 的多种作用 25 年。由于它们具有超长的寿命、增强的胰岛素敏感性和对多种与年龄相关疾病的保护作用，因此常被用于研究健康衰老。为了确定脂肪组织对 GHRKO 表型的影响，我们实验室最近创建并表征了脂肪细胞特异性 GHRKO (AdGHRKO) 小鼠，这些小鼠表现出脂肪量增加，但由于胰岛素敏感性增强，它们看起来健康。为了验证这样一种假设，即去除脂肪细胞中的 GH 作用可能部分复制在全身性 GHRKO 小鼠中观察到的寿命延长和健康寿命延长，我们评估了两性衰老 AdGHRKO 小鼠的肥胖程度、细胞因子/脂肪因子、葡萄糖稳态、虚弱和寿命。我们的研究结果表明，在脂肪细胞中破坏 GH 受体基因可改善老年时的胰岛素敏感性，并延长雄性 AdGHRKO 小鼠的寿命。AdGHRKO 小鼠还表现出脂肪量增加、循环胰岛素、C 肽、脂联素、抵抗素水平降低，以及在老年时握力增加的虚弱评分改善。将发表的 GHRKO 小鼠平均寿命数据与 AdGHRKO 和肌肉特异性 GHRKO 小鼠的数据进行比较表明，雄性 GHRKO 中大约 23%的寿命延长归因于脂肪细胞中 GHR 的破坏，而在肌肉中则为大约 19%。在这两种组织中，雌性从 GHR 的破坏中获益较少，分别为大约 19%和大约 0%。这些数据表明，即使在单一组织中去除 GH 的作用，也足以带来可观察到的健康益处，这些益处可促进长期健康、减少虚弱和延长寿命。
