David Spanswick

Bio: David Spanswick is an academic researcher from University of Warwick. The author has contributed to research in topics: Long-term potentiation & Hyperpolarization (biology). The author has an hindex of 27, co-authored 80 publications receiving 3820 citations. Previous affiliations of David Spanswick include Coventry Health Care & University of Aberdeen.

Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels

Abstract: Leptin, the protein encoded by the obese (ob) gene, is secreted from adipose tissue and is thought to act in the central nervous system to regulate food intake and body weight. It has been proposed that leptin acts in the hypothalamus, the main control centre for satiety and energy expenditure. Mutations in leptin or the receptor isoform (Ob-R[L]) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes. Here we show that leptin hyperpolarizes glucose-receptive hypothalamic neurons of lean Sprague-Dawley and Zucker rats, but is ineffective on neurons of obese Zucker (fa/fa) rats. This hyperpolarization is due to the activation of a potassium current, and is not easily recovered on removal of leptin, but is reversed by applying the sulphonylurea, tolbutamide. Single-channel recordings demonstrate that leptin activates an ATP-sensitive potassium (K[ATP]) channel. Our data indicate that the K(ATP) channel may function as the molecular end-point of the pathway following leptin activation of the Ob-R(L) receptor in hypothalamic neurons.

Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats.

Abstract: Insulin and leptin receptors are present in hypothalamic regions that control energy homeostasis, and these hormones reduce food intake and body weight in lean, but not obese, Zucker rats. Here we demonstrate that insulin, like leptin, hyperpolarizes lean rat hypothalamic glucose-responsive (GR) neurons by opening KATP channels. These findings suggest hypothalamic K ATP channel function is crucial to physiological regulation of food intake and body weight.

Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus.

Abstract: The hypothalamic arcuate nucleus (ARC) integrates and responds to satiety and hunger signals and forms the origins of the central neural response to perturbations in energy balance. Here we show that rat ARC neurons containing neuropeptide Y (NPY) and agouti-related protein (AgRP), which are conditional pacemakers, are activated by orexigens and inhibited by the anorexigen leptin. We propose a neuron-specific signaling mechanism through which central and peripheral signals engage the central neural anabolic drive.

The role of amino acid neurotransmitters in the regulation of pituitary gonadotropin release in fish.

Abstract: Both glutamate and γ-aminobutyric acid (GABA) are involved in pituitary hormone release in fish. Glutamate serves 2 purposes, both as a neurotransmitter and as a precursor for GABA synthesis. Gluta...

Central nervous system control of food intake

Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

Leptin and the regulation of body weight in mammals

Abstract: The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution However, the presence of excess adipose tissue can be maladaptive A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system Leptin also signals nutritional status to several other physiological systems and modulates their function Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity

Neuroscience 細胞死：最近の知見

Abstract: 中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Central nervous system control of food intake and body weight

Abstract: The capacity to adjust food intake in response to changing energy requirements is essential for survival. Recent progress has provided an insight into the molecular, cellular and behavioural mechanisms that link changes of body fat stores to adaptive adjustments of feeding behaviour. The physiological importance of this homeostatic control system is highlighted by the severe obesity that results from dysfunction of any of several of its key components. This new information provides a biological context within which to consider the global obesity epidemic and identifies numerous potential avenues for therapeutic intervention and future research.

Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus

Abstract: The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.