Why leptin keeps you warm.
Why leptin keeps you warm.
复制标题
为什么瘦素可以让你保持温暖。
DOI：
10.1016/j.molmet.2014.09.007
复制
发表时间：
2014
影响因子：
8.1
通讯作者：
Buettner,Christoph
中科院分区：
文献类型：
--
作者：
Jo,Young-Hwan;Buettner,Christoph
If a good layer of insulating fat would be sufficient to stay warm, leptin deficient ob/ob mice should do fine in a cold environment since they are massively obese. But once exposed to low temperatures, ob/ob mice rapidly die of hypothermia. Even at ambient temperatures ob/ob mice have a core body temperature that is 2 C lower than that of wild type littermates [1]. This hypothermia can be normalized through the administration of leptin [2] demonstrating that leptin action controls thermogenesis. Since the thermogenic effects of leptin are an important contributor to its anti-obesity properties, it is important to understand this basic biology from a clinical standpoint. How and where does leptin regulate thermogenesis? Brown adipose tissue (BAT) is the designate tissue for thermogenesis in mammals, including humans, as it has the unique ability to uncouple respiration from ATP production. BAT activity is centrally regulated through the sympathetic nervous system. Key areas in the central nervous system that regulate BAT activity appear to be the median preoptic subnucleus (MnPO) of the preoptic area (POA). Both cool and warm cutaneous thermosensory signals are transmitted from the spinal dorsal horn to the POA via neurons in the lateral parabrachial nucleus (LPB)[3]. Neurons in the MnPO project to sympathetic premotor neurons in the rostral raphe pallidus (rRPa) to regulate sympathetic BAT inputs. In addition to this MnPO-rRPa pathway regulating BAT thermogenesis, prior studies have reported that neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DHA) also participate in the regulation of BAT activity [4]. Moreover, it has been described that leptin receptor-expressing neurons in the DMH increase sympathetic outflow to BAT and vice versa and that the injection of leptin into the DMH/DHA normalized body temperature in ob/ob [5], suggesting that leptin normalizes energy expenditure by inducing BAT activation and thermogenesis via neurons in the DMH/DHA. In the last issue of Molecular Metabolism, Rezai-Zadeh and colleagues report that the injection of leptin into the DMH/DHA restores core body temperature and increases locomotor activity in leptin deficient ob/ob mice [6], providing a striking example of the role of leptin signaling within the DMH/DHA in regulating energy expenditure. To define the role of leptin receptor expressing (LepRb) neurons in the DMH/DHA, the authors selectively activated these neurons via DREADDs, which are mutated muscarinic receptors that lack responsiveness for acetylcholine but respond to an otherwise inert drug, clozapine-N-oxide. This technique allows one to probe the role of LepRb neurons within the DMH/DHA in the regulation of biological pathways, which is distinct from asking what leptin signaling does in these neurons. After only three days of activation of DMH/DHA LepRb neurons via DREADDs, mice lost body weight, which was only partially reduced after b3-adrenergic blockade. Conversely, deletion of the leptin receptor from DMH/DHA neurons promoted body weight gain by reducing energy expenditure, illustrating the physiological importance of DMH/DHA LepRb neurons and leptin signaling in these neurons in the regulation of whole body energy homeostasis. Of particular interest is the finding that DMH/DHA LepRb neurons directly project to the raphe pallidus that contains sympathetic premotor neurons [7]. The activation of DMH/DHA LepRb neurons increased BAT thermogenesis, which suggests that LepRb neurons in the DMH/DHA provide excitatory synaptic inputs to rostral raphe pallidus neurons. Indeed, a recent study by Nakamura’s group clearly demonstrates …
