我们之前已经表明,小鼠食用低碳水化合物生酮饮食(KD)会导致与体重减轻相关的独特生理状态,代谢率增加,改善胰岛素敏感性[1]。此外,我们确定成纤维细胞生长因子21(FGF21)作为变化的必要介质,缺乏FGF21饲喂KD的小鼠体重增加而不是减肥[2]。FGF21激活交感神经系统(SNS)[3],是代谢率的关键调节因子.因此,我们认为SNS可能在介导酮症的代谢适应中起作用。
为了检验这一假设,我们测量了缺乏所有三种β-肾上腺素能受体的小鼠(β-少小鼠)对KD喂养的反应。
与野生型(WT)对照相比,无β小鼠体重增加,脂肪组织库块增加,消耗KD时没有增加能量消耗。值得注意的是,尽管体重增加,无β小鼠对胰岛素敏感。KD诱导的β减少小鼠肝基因表达的变化与吃KD的WT对照组相似。在饲喂KD的WT和β少小鼠中,FGF21mRNA的表达上升了60倍以上,和相应的循环FGF21水平在KD喂养的野生型对照中为12.5ng/ml,在KD喂养的β-少小鼠中为35.5ng/ml。
无β小鼠的反应区分了消耗KD的小鼠中至少两个不同类别的生理效应。在肝脏中,KD通过独立于SNS和β-肾上腺素能受体的FGF21的作用调节过氧化物酶体增殖物激活受体α(PPARα)依赖性途径。与此形成鲜明对比的是,肩胛骨间棕色脂肪组织(BAT)的诱导和增加的能量消耗绝对需要涉及对一种或多种β-肾上腺素能受体的作用的SNS信号。这样,FGF21响应KD的关键代谢作用具有不同的效应机制。
We have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate. Thus, we considered that the SNS may play a role in mediating the metabolic adaption to ketosis.
To test this hypothesis, we measured the response of mice lacking all three β-adrenergic receptors (β-less mice) to KD feeding.
In contrast to wild-type (WT) controls, β-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, β-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of β-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and β-less mice fed KD, and corresponding circulating FGF21 levels were 12.5 ng/ml in KD-fed wild type controls and 35.5 ng/ml in KD-fed β-less mice.
The response of β-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT) and increased energy expenditure absolutely require SNS signals involving action on one or more β-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms.