Edison Biotechnology Institute (T.Y., L.A.H., E.R.L., E.O.L., K.T., C.V., S.D.-O., J.J.K., D.E.B.), School of Applied Health Sciences and Wellness, College of Health Sciences and Professions (T.Y., L.A.H., K.T., S.D.-O., D.E.B.), and Department of Biomedical Sciences (J.K., D.E.B.), Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701.
Endocrinology. 2015 Feb;156(2):555-64. doi: 10.1210/en.2014-1617. Epub 2014 Nov 18.
Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction in GH action and HF diet. In conclusion, our findings show that GHA mice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis.
尽管在多种小鼠品系中，生长激素（GH）水平降低与改善葡萄糖代谢和延长寿命有关，但 GH 受体拮抗剂（GHA）转基因小鼠却违背了这一趋势，因为它的 GH 作用降低，脂肪量增加，但葡萄糖代谢和寿命与对照相似。在高脂肪（HF）饮食下，葡萄糖代谢和脂肪量谱的细微差异可能会变得更加明显。因此，在这项研究中，10 周龄时开始，将 C57BL/6 背景下的雄性和雌性 GHA 和野生型（WT）小鼠置于 HF 和低脂肪（LF）饮食中 11 周，以评估 GHA 小鼠对 HF 喂养额外代谢应激的反应。在 HF 饮食中，所有小鼠体重均明显增加，尽管 GHA 小鼠比 WT 小鼠增加得更明显，雄性比雌性增加得更多。体重增加主要归因于脂肪量的增加，WT 小鼠主要增加在白色脂肪组织腹股沟脂肪组织中，而 GHA 小鼠则在白色脂肪组织的腹股沟和腹股沟外区域均有增加。值得注意的是，GHA 小鼠对 HF 饮食的葡萄糖代谢不良变化有一定的保护作用，因为它们的血清葡萄糖水平仅适度升高，仍然耐糖，并且没有发生高胰岛素血症。在许多测量指标中都观察到了性别差异，雄性对 GH 作用降低和 HF 饮食的反应更为明显。总之，我们的研究结果表明，已经肥胖的 GHA 小鼠在 HF 喂养时易发生进一步的脂肪组织扩张，同时对葡萄糖稳态的改变保持弹性。
