Neuronal control of energy homeostasis

Neuronal control of body energy homeostasis is the key mechanism by which animals and humans regulate their long-term energy balance. Various hypothalamic neuronal circuits (which include the hypothalamic melanocortin, midbrain dopamine reward and caudal brainstem autonomic feeding systems) control energy intake and expenditure to maintain body weight within a narrow range for long periods of a life span. Numerous peripheral metabolic hormones and nutrients target these structures providing feedback signals that modify the default "settings" of neuronal activity to accomplish this balance. A number of molecular genetic tools for manipulating individual components of brain energy homeostatic machineries, in combination with anatomical, electrophysiological, pharmacological and behavioral techniques, have been developed, which provide a means for elucidating the complex molecular and cellular mechanisms of feeding behavior and metabolism. This review will highlight some of these advancements and focus on the neuronal circuitries of energy homeostasis.     

脂肪组织中自噬信号通路及其功能

细胞自噬是一种真核生物中高度保守的代谢过程,包括巨自噬、微自噬以及分子伴侣介导的自噬等。自噬过程可以清除受损的细胞器,降解糖原、脂类和蛋白质等生物大分子物质,供细胞重新利用,维持细胞内代谢平衡。自噬障碍与多种疾病的病理发生过程息息相关,包括肿瘤、2型糖尿病、肥胖、骨骼肌病以及神经退行性疾病等。脂肪组织是人体脂质储存的重要场所,广泛分布于全身各处,如内脏和皮下等。脂肪组织通过储存冗余脂肪并分泌脂肪因子,防止脂肪的异位堆积和脂毒性的发生,维持机体的脂质稳态。近期的许多研究表明,自噬进程深度参与脂肪细胞的细胞分化与能量代谢。因此,深入探究脂肪组织自噬过程与机体脂质稳态的调控关系,有利于揭示机体脂质平衡的内在机制,为新型药物靶点的开发提供扎实的理论依据和数据支持。本文就近年来关于自噬影响脂肪组织脂质代谢的最新研究进展作一综述。     

Oxysterols in human circulation: which role do they have?

Oxysterols are oxygenated derivatives of cholesterol that are intermediates in cholesterol excretion pathways. They may also be regarded as transport forms of cholesterol and introduction of an additional hydroxyl group facilitates flux of cholesterol across cell membranes and the blood-brain barrier. According to current concepts, oxysterols are also mediating a number of cholesterol-induced metabolic effects. The recent discovery of nuclear receptors with an affinity for oxysterols has given support to this concept. Nuclear receptors such as liver X receptor alpha do have a role in cholesterol homeostasis, but there is still only indirect evidence that oxysterols are the physiological ligands. In this overview we report some recent advancements in our knowledge about the origin and metabolic fate of the quantitatively most important oxysterols occurring in the circulation. In addition, we discuss the possibility that some of these oxysterols may activate liver X receptors and regulate cholesterol homeostasis.     

Gap junction and hemichannel-independent actions of connexins on cell and tissue functions – An update

Connexins, a family of transmembrane proteins, are components of both gap junction channels and hemichannels, which mediate the exchange of ions and small molecules between adjacent cells, and between the inside and outside of the cell, respectively. Substantial advancements have been made in the comprehension of the role of gap junctions and hemichannels in coordinating cellular events. In recent years, a plethora of studies demonstrate a role of connexin proteins in the regulation of tissue homeostasis that occurs independently of their channel activities. This is shown in the context of cell growth, adhesion, migration, apoptosis, and signaling. The major mechanisms of these channel-independent activities still remain to be discovered. In this review, we provide an updated overview on the current knowledge of gap junction- and hemichannel-independent functions of connexins, in particular, their effects on tumorigenesis, neurogenesis and disease development.     

Mitochondrial creatine kinase in human health and disease

Mitochondrial creatine kinase (MtCK), together with cytosolic creatine kinase isoenzymes and the highly diffusible CK reaction product, phosphocreatine, provide a temporal and spatial energy buffer to maintain cellular energy homeostasis. Mitochondrial proteolipid complexes containing MtCK form microcompartments that are involved in channeling energy in form of phosphocreatine rather than ATP into the cytosol. Under situations of compromised cellular energy state, which are often linked to ischemia, oxidative stress and calcium overload, two characteristics of mitochondrial creatine kinase are particularly relevant: its exquisite susceptibility to oxidative modifications and the compensatory up-regulation of its gene expression, in some cases leading to accumulation of crystalline MtCK inclusion bodies in mitochondria that are the clinical hallmarks for mitochondrial cytopathies. Both of these events may either impair or reinforce, respectively, the functions of mitochondrial MtCK complexes in cellular energy supply and protection of mitochondria form the so-called permeability transition leading to apoptosis or necrosis.     

Modeling metabolic homeostasis and nutrient sensing in Drosophila: implications for aging and metabolic diseases

Over the past decade, numerous reports have underscored the similarities between the metabolism of Drosophila and vertebrates, with the identification of evolutionarily conserved enzymes and analogous organs that regulate carbohydrate and lipid metabolism. It is now well established that the major metabolic, energy-sensing and endocrine signaling networks of vertebrate systems are also conserved in flies. Accordingly, studies in Drosophila are beginning to unravel how perturbed energy balance impinges on lifespan and on the ensuing diseases when energy homeostasis goes awry. Here, we highlight several emerging concepts that are at the nexus between obesity, nutrient sensing, metabolic homeostasis and aging. Specifically, we summarize the endocrine mechanisms that regulate carbohydrate and lipid metabolism, and provide an overview of the neuropeptides that regulate feeding behavior. We further describe the various efforts at modeling the effects of high-fat or -sugar diets in Drosophila and the signaling mechanisms involved in integrating organ function. Finally, we draw attention to some of the cardinal discoveries made with these disease models and how these could spur new research questions in vertebrate systems.KEY WORDS: Metabolic homeostasis, Nutrient sensing, Drosophila     

The role of the vgf gene and VGF-derived peptides in nutrition and metabolism

Energy homeostasis is a complex physiological function coordinated at multiple levels. The issue of genetic regulation of nutrition and metabolism is attracting increasing interest and new energy homeostasis-regulatory genes are continuously identified. Among these genes, vgf is gaining increasing interest following two observations: (1) VGF-/- mice have a lean and hypermetabolic phenotype; (2) the first VGF-derived peptide involved in energy homeostasis, named TLQP-21, has been identified. The aim of this review will be to discuss the role of the vgf gene and VGF derived peptides in metabolic and nutritional functions. In particular we will: (1) provide a brief overview on the central systems regulating energy homeostasis and nutrition particularly focusing on the melanocortin system; (2) introduce the structure and molecular characteristic of vgf; (3) describe the phenotype of VGF deficient mice; (4) present recent data on the metabolic role of VGF-derived peptides, particularly focusing on one peptide named TLQP-21.     

Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis

Dopaminergic midbrain neurons integrate signals on food palatability and food-associated reward into the complex control of energy homeostasis. To define the role of insulin receptor (IR) signaling in this circuitry, we inactivated IR signaling in tyrosine hydroxylase (Th)-expressing cells of mice (IR(ΔTh)). IR inactivation in Th-expressing cells of mice resulted in increased body weight, increased fat mass, and hyperphagia. While insulin acutely stimulated firing frequency in 50% of dopaminergic VTA/SN neurons, this response was abolished in IR(ΔTh) mice. Moreover, these mice exhibited an altered response to cocaine under food-restricted conditions. Taken together, these data provide in?vivo evidence for a critical role of insulin signaling in catecholaminergic neurons to control food intake and energy homeostasis.     

Synphilin-1 Binds ATP and Regulates Intracellular Energy Status

Recent studies have suggested that synphilin-1, a cytoplasmic protein, is involved in energy homeostasis. Overexpression of synphilin-1 in neurons results in hyperphagia and obesity in animal models. However, the mechanism by which synphilin-1 alters energy homeostasis is unknown. Here, we used cell models and biochemical approaches to investigate the cellular functions of synphilin-1 that may affect energy balance. Synphilin-1 was pulled down by ATP-agarose beads, and the addition of ATP and ADP reduced this binding, indicating that synphilin-1 bound ADP and ATP. Synphilin-1 also bound GMP, GDP, and GTP but with a lower affinity than it bound ATP. In contrast, synphilin-1 did not bind with CTP. Overexpression of synphilin-1 in HEK293T cells significantly increased cellular ATP levels. Genetic alteration to abolish predicted ATP binding motifs of synphilin-1 or knockdown of synphilin-1 by siRNA reduced cellular ATP levels. Together, these data demonstrate that synphilin-1 binds and regulates the cellular energy molecule, ATP. These findings provide a molecular basis for understanding the actions of synphilin-1 in energy homeostasis.     

Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat

Energy stores are held relatively constant in many mammals. The circuitry necessary for maintaining energy homeostasis should (1) sense the amount of energy stored in adipose tissue, (2) sense and integrate the multiple opposing signals regarding nutritional state, and (3) provide output regulating energy intake and expenditure to maintain energy homeostasis. We demonstrate that individual neurons within the paraventricular nucleus of the hypothalamus (PVH) are capable of detection and integration of orexigenic (neuropeptide Y [NPY]) and anorexigenic (melanocortin) signals, that NPY and melanocortins are functional antagonists of each other within the PVH in the regulation of feeding behavior, and that melanocortin administration within the PVH regulates both feeding behavior and energy expenditure. These data provide a cellular basis for the adipostat within neurons in the PVH that appear to be jointly regulated by NPY- and melanocortin-responsive neurons.     

Functional Heterogeneity of Arcuate Nucleus Pro-Opiomelanocortin Neurons: Implications for Diverging Melanocortin Pathways

Arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons are essential regulators of food intake, energy expenditure, and glucose homeostasis. POMC neurons integrate several key metabolic signals that include neurotransmitters and hormones. The change in activity of POMC neurons is relayed to melanocortin receptors in distinct regions of the central nervous system. This review will summarize the role of leptin and serotonin receptors in regulating the activity of POMC neurons and provide a model in which different melanocortin pathways regulate energy and glucose homeostasis.     

神经元稳态失衡和饮食诱导肥胖症的相关性研究进展

近年来,因肥胖症所造成的社会问题和医疗负担越发严重。肥胖主要是由于机体能量的摄入与消耗不平衡所致,而中枢神经系统以及相关神经元在机体能量代谢平衡的调控中发挥着重要作用。下丘脑弓状核含有抑食性阿黑皮素原(Proopiomelanocortin,POMC)神经元和促食性神经肽Y (Neuropeptid Y,NPY)/刺鼠相关蛋白(Agouti-related protein,AgRP)神经元,是调控机体摄食行为的主要神经元。研究显示,高脂饮食会诱导POMC神经元中的Rb蛋白发生磷酸化修饰并失活,导致POMC神经元从静息状态重新进入细胞周期循环,进而迅速转向细胞凋亡。高脂饮食也会引起神经元再生抑制,并诱导炎症发生和神经元损伤,使神经元稳态失衡,引发瘦素抵抗,最终导致肥胖症的发生。文中就神经元稳态失衡以及肥胖症等疾病之间的关系进行了综述,希望能为饮食诱导肥胖症等疾病的治疗和预防提供新的方向和思路。     

Advanced Design of Light-Assisted Nanogenerators with Multifunctional Perovskites

Enormous efforts are invested in developing multi-energy harvesting technology with simple configuration and high conversion efficiency, and light-assisted nanogenerators are considered a promising solution. Multifunctional perovskites are explored for this light-assisted nanogenerator, owing to its powerful platform characteristics for integrating multiple energy conversion mechanisms and multi-effects coupling phenomenon. Therefore, with the rapid progress of this emerging field, a timely and comprehensive review of this light-assisted nanogenerator is urgently needed for updating the fundamental understanding of coupling mechanism and material-device-performance relationship. In this review, recent advancements of the perovskite light-assisted nanogenerator with their advanced designs are presented. First, the fundamental properties co-existing in perovskites are briefly introduced, as well as some emerging effects (e.g., flexoelectric). Subsequently, the further coupling mechanism between photovoltaic effect and other energy conversion effects in different light-assisted nanogenerator are discussed in categories. And the output characteristics and potential application of various coupled devices are systematically described from the perspective of perovskites selection and device engineering. Finally, some perspectives on existing challenges and further development for light-assisted nanogenerator are put forward, with the aim to provide useful guidance for the design of advanced devices.     

Animals models of MCH function and what they can tell us about its role in energy balance

Melanin-concentrating hormone (MCH) has attracted considerable attention because of its effects on food intake and body weight and the MCH receptor (MCHR1) remains one of the viable targets for obesity therapy. This review summarizes the literature examining the effects of MCH on body weight, food intake and energy expenditure in rodent models, and the central sites where MCH acts in regulating energy homeostasis. Emphasis is given on the discrepancies between the genetic and pharmacologic models of MCHR1 inactivation. We propose some solutions to resolve these discrepancies and discuss some future directions in MCH research.     

Bone morphogenic proteins signaling in adipogenesis and energy homeostasis

A great deal is known about the molecular mechanisms regulating terminal differentiation of pre-adipocytes into mature adipocytes. In contrast, the knowledge about pathways that trigger commitment of mesenchymal stem cells into the adipocyte lineage is fragmented. In recent years, the role of members of the bone morphogenic protein family in regulating the early steps of adipogenesis has been the focus of research. Findings based on these studies have also highlighted an unexpected role for some bone morphogenic protein in energy homeostasis via regulation of adipocyte development and function. This review summarizes the knowledge about bone morphogenic proteins and their role in adipocyte commitment and regulation of whole body energy homeostasis. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.     

A Boolean probabilistic model of metabolic adaptation to oxygen in relation to iron homeostasis and oxidative stress

Background  

In aerobically grown cells, iron homeostasis and oxidative stress are tightly linked processes implicated in a growing number of diseases. The deregulation of iron homeostasis due to gene defects or environmental stresses leads to a wide range of diseases with consequences for cellular metabolism that remain poorly understood. The modelling of iron homeostasis in relation to the main features of metabolism, energy production and oxidative stress may provide new clues to the ways in which changes in biological processes in a normal cell lead to disease.     

Genome of alkaliphilic Bacillus pseudofirmus OF4 reveals adaptations that support the ability to grow in an external pH range from 7.5 to 11.4

Bacillus pseudofirmus OF4 is an extreme but facultative alkaliphile that grows non-fermentatively in a pH range from 7.5 to above 11.4 and can withstand large sudden increases in external pH. It is a model organism for studies of bioenergetics at high pH, at which energy demands are higher than at neutral pH because both cytoplasmic pH homeostasis and ATP synthesis require more energy. The alkaliphile also tolerates a cytoplasmic pH?>?9.0 at external pH values at which the pH homeostasis capacity is exceeded, and manages other stresses that are exacerbated at alkaline pH, e.g. sodium, oxidative and cell wall stresses. The genome of B.?pseudofirmus OF4 includes two plasmids that are lost from some mutants without viability loss. The plasmids may provide a reservoir of mobile elements that promote adaptive chromosomal rearrangements under particular environmental conditions. The genome also reveals a more acidic pI profile for proteins exposed on the outer surface than found in neutralophiles. A large array of transporters and regulatory genes are predicted to protect the alkaliphile from its overlapping stresses. In addition, unanticipated metabolic versatility was observed, which could ensure requisite energy for alkaliphily under diverse conditions.     

Peripheral influences on central melanocortin neurons

The melanocortins are peptide products of post-translational processing of the pro-opiomelanocortin precursor protein. Melanocortin-expressing neurons are found in the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract in the brain stem. The central melanocortin system is involved in a number of biological functions, including regulation of energy homeostasis. Hypothalamic and brain stem circuits interpret and integrate a number of peripheral inputs to provide a coordinated central response. This review examines the effect of these peripheral signals on central melanocortin signaling.     

AMPK: a metabolic gauge regulating whole-body energy homeostasis

AMP-activated protein kinase (AMPK) is the downstream component of a kinase cascade that acts as a gauge of cellular energy levels. Over the last few years, accumulating evidence has demonstrated that AMPK is also involved in the regulation of energy balance at the whole-body level by responding to hormones and nutrient signals, which leads to changes in energy homeostasis. The physiological relevance of this new role of AMPK is demonstrated by the fact that impairment of AMPK function is associated with metabolic alterations, insulin resistance, obesity, hormonal disorders and cardiovascular disease. Here, we summarize the role of AMPK in the regulation of energy homeostasis. Understanding this key enzyme and its tissue-specific regulation will provide new targets for the treatment of metabolic disorders.