Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, and Diabetes Institute, Ohio University, Athens, OH 45701, USA.
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237, USA.
Int J Mol Sci. 2023 Feb 20;24(4):4231. doi: 10.3390/ijms24044231.
Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice.
饮食中的脂质会诱导载脂蛋白 A4（APOA4）的产生和棕色脂肪组织（BAT）的产热。在给予 Chow 饮食的小鼠中，外源性 APOA4 的给予会增加 BAT 的产热，但在给予高脂肪饮食（HFD）的小鼠中则不然。慢性给予 HFD 会减弱野生型（WT）小鼠的血浆 APOA4 产生和 BAT 产热。鉴于这些观察结果，我们试图确定稳定的 APOA4 产生是否可以保持 BAT 产热升高，即使在消耗 HFD 的情况下，最终目的是降低体重、脂肪量和血浆脂质水平。在小肠中过表达小鼠 APOA4 的转基因小鼠（APOA4-Tg 小鼠）比其 WT 对照产生更多的血浆 APOA4，即使给予动脉粥样硬化饮食也是如此。因此，我们使用这些小鼠来研究在消耗 HFD 期间 APOA4 和 BAT 产热之间的相关性。本研究的假设是，在小肠中过表达小鼠 APOA4 和增加血浆 APOA4 的产生会增加 BAT 的产热，从而减少 HFD 喂养肥胖小鼠的脂肪量和血浆脂质。为了验证这一假设，我们测量了雄性 APOA4-Tg 小鼠和 WT 小鼠在给予 Chow 饮食或 HFD 时的 BAT 产热蛋白、体重、脂肪量、热量摄入和血浆脂质。当给予 Chow 饮食时，APOA4 水平升高，血浆甘油三酯（TG）水平降低，BAT 中的 UCP1 水平呈上升趋势，而 APOA4-Tg 和 WT 小鼠的体重、脂肪量、热量摄入和血浆脂质相当。在 HFD 喂养四周后，APOA4-Tg 小鼠保持了升高的血浆 APOA4 和降低的血浆 TG，但与 WT 对照组相比，BAT 中的 UCP1 水平显著升高；体重、脂肪量和热量摄入仍然相当。然而，在 10 周 HFD 消耗后，尽管 APOA4-Tg 小鼠仍表现出升高的血浆 APOA4、UCP1 水平和降低的 TG 水平，但与 WT 对照组相比，体重、脂肪量和血浆脂质及瘦素水平最终降低，且不依赖于热量摄入。此外，在 10 周 HFD 喂养期间的几个时间点测量时，APOA4-Tg 小鼠的能量消耗增加。因此，在小肠中过表达 APOA4 和维持升高的血浆 APOA4 水平似乎与 UCP1 依赖性 BAT 产热的升高相关，随后可防止小鼠发生 HFD 诱导的肥胖。
