Energy signaling in obese mice delays the impact of fasting on thermoregulation

S. Maloney
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Abstract

I thank the editors of Temperature for the opportunity to provide an editorial comment on the recent article by Solym ar et al. We have known for some time that, when endothermic animals are fasted, their energy expenditure pathways are altered in a way that results in a decrease in core body temperature during the inactive phase of their daily activity cycle. The decrease in body temperature generally is viewed as adaptive, since the closer the animal’s body temperature is to ambient temperature, the less energy is required to defend body temperature. In the laboratory mouse, a few days of fasting takes body temperature to below 31 C, which, according to the definition employed in the paper under discussion, means that the mice enter torpor. There is no change (at least initially) in the core body temperature during the active phase of the daily cycle; that is counterintuitive but seems to be what occurs to the body temperature rhythm whenever mammals run low on energy. Mammals with normal body fat content run low on energy soon after starting to fast, and display heterothermy within a day or two of fast initiation. What happens to obese animals, which have a store of energy in body fat? That is what Solym ar et al. have investigated, for the first time. In the face of a complete fast, mice previously made obese did not enter torpor until their body mass approached that of the normal-mass mice, a process that took several weeks; the obese mice started with a body mass more than double that of the control lean mice Figure. 2 of the paper by Solym ar and colleagues shows, though, that less-dramatic but distinct changes in the temperature rhythm of the obese mice happened long before that, as do cardiovascular changes in fasted obese mice. Indeed, heart rate, blood pressure, and oxygen consumption fell more rapidly during a fast in obese mice than they did in lean mice, albeit from a higher baseline. Thermal physiologists certainly would want to know what signal to the thermoregulatory system differed, during the first days of fasting, between the obese and lean animals. Neither the obese nor the lean mice were eating, and so presumably the gut-derived peptides that have been implicated in the shortterm control of appetite and energy expenditure did not differ. It would be valuable to test that hypothesis by measuring those peptides. A better candidate would be leptin, the adipose-derived cytokine that has been implicated in the hypothermia of fasting. Leptin replacement in underfed and ob/ob mice reduces the incidence of torpor, and mice without dopamine b hydroxylase (an enzyme in the pathway to epinephrine and norepinephrine production) show neither a fall in leptin nor torpor when fasted Though Solym ar and colleagues did not measure leptin concentrations in their mice, it seems quite possible that the obese mice, with surplus energy, had a delayed fall in leptin with fasting. There don’t appear to be any long-term data on leptin concentrations during fasting in mice previously made obese, a surprising hiatus in the literature, but high fat feeding blunts the fall in plasma leptin during fasting, at least during the initial 48 hours. But leptin cannot be the only mediator of the torpor response to fasting. Other mediators must exist because ob/ ob mice lack leptin, and db/db mice lack its receptor, and yet neither are permanently torpid. An alternative signal for the entry into torpor might be falling glucose levels. Overton and Williams summarise the evidence for a role
肥胖小鼠的能量信号传导延迟了禁食对体温调节的影响
感谢《温度》杂志的编辑们给我机会对Solym等人最近发表的文章发表评论。我们早就知道,当吸热动物禁食时,它们的能量消耗途径会发生改变,导致它们在日常活动周期的非活动阶段核心体温下降。体温的下降通常被认为是适应性的,因为动物的体温越接近环境温度,保护体温所需的能量就越少。在实验室小鼠中,禁食几天使体温降至31℃以下,根据本文的定义,这意味着小鼠进入了冬眠状态。在每日周期的活跃阶段,核心体温没有变化(至少最初没有变化);这是违反直觉的,但似乎是哺乳动物能量不足时体温节律发生的变化。身体脂肪含量正常的哺乳动物在开始禁食后很快就会消耗掉能量,并在禁食开始的一两天内表现出异温性。肥胖的动物会发生什么,它们的身体脂肪中储存着能量?这是Solym等人第一次进行的调查。在完全禁食的情况下,先前肥胖的老鼠直到它们的体重接近正常体重的老鼠时才会进入昏睡状态,这个过程需要几个星期;然而,索林及其同事的论文图2显示,肥胖老鼠的体重开始时是对照组瘦老鼠的两倍多,肥胖老鼠的体温节律发生了不那么剧烈但明显的变化,在此之前很久就发生了,禁食的肥胖老鼠的心血管变化也是如此。事实上,肥胖老鼠的心率、血压和耗氧量在禁食期间比瘦老鼠下降得更快,尽管基线更高。热生理学家当然想知道,在禁食的头几天,肥胖动物和瘦弱动物向体温调节系统发出的信号有什么不同。肥胖的老鼠和瘦弱的老鼠都没有进食,因此可以推测,与食欲和能量消耗的短期控制有关的肠道衍生肽并没有什么不同。通过测量这些肽来检验这个假设是很有价值的。一个更好的候选者是瘦素,一种脂肪来源的细胞因子,与禁食的低体温有关。在喂养不足的小鼠和ob/ob小鼠中,瘦素替代降低了昏睡的发生率,而缺乏多巴胺b羟化酶(一种肾上腺素和去甲肾上腺素产生途径中的酶)的小鼠在禁食时既没有显示出瘦素的下降,也没有显示出昏睡。尽管solyar和同事没有测量小鼠体内的瘦素浓度,但似乎很有可能是能量过剩的肥胖小鼠在禁食时瘦素的下降延迟了。在先前肥胖的小鼠中,似乎没有任何关于禁食期间瘦素浓度的长期数据,这在文献中是一个令人惊讶的空白,但高脂肪喂养会减缓禁食期间血浆瘦素的下降,至少在最初的48小时内是这样。但是瘦素并不是对禁食产生麻木反应的唯一媒介。其他介质肯定存在,因为ob/ ob小鼠缺乏瘦素,db/db小鼠缺乏瘦素受体,但两者都不是永久迟钝的。进入昏睡状态的另一个信号可能是血糖水平下降。奥弗顿和威廉姆斯总结了这一作用的证据
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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