for survival and reproduction , the body has developed an intricately balanced system to efficiently control energy homeostasis at multiple levels . in short , the brain continually monitors the systemic metabolic state and adjusts behavior , as well as humoral and neuronal outputs to peripheral effector organs , to ensure an appropriate energy supply . if the central nervous system ( cns ) senses a caloric shortage or surplus , the brain orchestrates responses that alter food intake , nutrient partitioning and physiological functions such as hepatic glucose production , adiposity and thermogenesis . efficient maintenance of the delicate homeostatic balance of energy , glucose and lipid metabolism largely depends on system - wide synchronicity of metabolic processes that can only be achieved by central regulatory influences and master circuits in the brain . disruption of such synchronicity , or failure of any of the key components of this system , are common pathophysiological causes of metabolic disorders such as obesity and diabetes . the most well - studied metabolic sensing region in the forebrain is the hypothalamus , where a number of nuclei such as the arcuate nucleus ( arc ) and ventromedial hypothalamus ( vmh ) express high levels of receptors that bind adipokines ( cell signaling molecules secreted by adipose tissue , such as leptin ) and gut hormones . central leptin resistance , one of the major causes of obesity , is caused by defective leptin sensing in these brain regions ( gautron and elmquist , 2011 ) . in the hindbrain , the nucleus tractus solitarius ( nts)dorsal motor nucleus of the vagus ( dmv ) complex is the best - studied brain area with respect to detection of metabolic feedback , especially from the gastrointestinal system via vagal afferents or the circulation ( berthoud et al . , 2006 ) . in this article and the accompanying poster , we provide an overview of current knowledge regarding coordinated system - wide connections that maintain energy homeostasis , highlighting how disruptions in metabolic sensing and integration between the brain , white adipose tissue ( wat ) and the gastrointestinal system can contribute to metabolic disorders . adipose - tissue communication pathways , it is important to acknowledge that other important cns - peripheral communications ( such as those involving muscle and brown adipose tissue ) also contribute to energy homeostasis . during embryogenesis , the parasympathetic ganglia of both the gut and the brain originate from the neural crest . this common origin could explain why many gut - secreted hormones and peptides and their receptors are also found in the brain ; indeed , many hormones produced by the gastrointestinal tract are referred to as brain - gut hormones . energy homeostasis can be well maintained only when the brain - gut circuit is synchronized . this synchronization is achieved by neuronal and humoral interaction between the brain and gut . in the gastrointestinal tract , nutrient digestion and absorption trigger the secretion of gut satiety signals such as cholecystokinin ( cck ) , peptide yy ( pyy ) and glucagon like peptide-1 ( glp-1 ) for stimulation of vagal sensory nerves to provide feedback to the brain ( berthoud , 2008 ) . vagal sensory terminals also express receptors for other gut hormones and peptides that are involved in metabolic regulation . the nts in the hindbrain is one of the major processors of vagal afferent signals , as evidenced by the finding that upper intestinal lipids inhibit hepatic glucose production through a vagal - nts circuit ( wang et al , 2008 ) . additionally , gut hormones and nutrients can influence several specific brain regions and neurons via the circulation . these factors reach these regions and neurons via transporters across either the blood - brain barrier ( bbb ) and/or less bbb - protected circumventricular organs where neurons can sense blood - borne signals more directly ( cottrell and ferguson , 2004 ; gross , 1992 ) . among these regions , the nts  area postrema ( ap ) complex in the hindbrain and the arc in the forebrain are two of the major targets of gut hormones ; insulin , produced in the pancreas , and ghrelin , produced in the stomach , are among the best studied gut hormones acting in these brain areas ( kojima et al . , 1999 ; obici et al . , 2002 ; pocai et al . , 2005 ; tschp et al . , 2000 ) . in response to gut hormones and nutrient signals , these brain areas relay the information to other key regulatory areas , such as the paraventricular nucleus ( pvh ) of the hypothalamus ( to maintain systemic metabolic homeostasis by modulating neuroendocrine and autonomic outputs ) and the suprachiasmatic nuclei [ scn ; where the central biological clock is located ( yi et al . , 2006 ) ] ( to synchronize the behavior and physiology of the whole body and balance the sympathetic and parasympathetic autonomic outflow ) . defective or weakened signal feedback by the brain in response to satiety and nutrients from the gut could cause over - feeding and dis - inhibition of liver glucose production , and thereby promote metabolic diseases ( berthoud , 2002 ) . the autonomic system uses sympathetic and parasympathetic outflow to balance peripheral energy production and expenditure . pre - autonomic neurons located in the pvh project to the lower autonomic centers in the hindbrain and spinal cord and mediate autonomic outflow to different parts of the gut system . good examples of these autonomic - center  gut connections are the parasympathetic outflow conveying the central insulin effect on liver glucose production ( obici et al . , 2002 ; pocai et al . , 2005 ) , and the central glucose - sensing effect on liver lipoprotein secretion ( lam et al . , 2007 ) . in contrast , activation of the sympathetic nervous system normally antagonizes peripheral insulin sensitivity . in wat , this antagonism triggers free fatty acid ( ffa ) release ; in liver , it stimulates glucose production via gluconeogenesis and glycogenolysis ; in muscle , it increases ffa oxidation , decreases glucose oxidation and glycogen synthesis , and results in reduced glucose uptake . abnormal elevation of sympathetic outflow could be caused by overactivation of orexin neurons under conditions of sleep deprivation ( yi et al . , 2009 ) , lack of inhibition of neuropeptide y neurons in the arc in the mediobasal hypothalamus ( van den hoek et al . , 2008 ) , or dysregulation of the melanocortin receptor in diverse populations of cells in the forebrain and hindbrain ( skibicka and grill , 2009 ) . feedback from gut hormones to the hypothalamic autonomic control center in the pvh can also influence neuroendocrine output . most of the neuroendocrine - derived hormones ( e.g. epinephrine , glucocorticoids , thyroid hormones and growth hormone ) also counteract insulin s action in the liver and other tissues ( yi et al . , 2010 ) . adipose tissue not only dynamically accumulates and releases lipids , but also acts as an endocrine organ . adipose tissue produces adipokines that inform the brain about whole - body long - term energy - storage status , and the tissue drives the brain s control of energy balance and the long - term regulation of body weight . in terms of adipose tissue crosstalk with the cns , the best studied adipokine is leptin ( halaas et al . , 1995 ; maffei et al . , 1995 ) , although adiponectin , resistin and apelin are also well studied with respect to their specific signaling pathways and functionalities in the cns ( banerjee et al . , 2004 ; , 2012 ; rajala et al . , 2004 ; singhal et al . , 2007 ; it is not yet clear whether other adipokines , including those recently identified [ such as retinol binding protein 4 ( rbp4 ) , visfatin and omentin ] , are involved in adipose - tissue  brain communication . in addition to adipokines , wat also communicates with the brain via neuronal inputs ( bartness et al . , 2010b ) . the inability to sense leptin signals ( leptin resistance ) in key areas in the hypothalamus and hindbrain is thought to be one of the underlying mechanisms in the development of obesity . generally , leptin resistance can cause the brain to misunderstand long - term energy stores and , as a result , initiate extra energy production i.e. overfeeding ( hyperphagia ) and glucose production ( hyperglycemia ) , which are typical symptoms of metabolic disorders . the dominant autonomic - wat connections are neuronal sympathetic outputs that initiate lipid mobilization in wat . this sympathetic outflow can be generated from the higher autonomic center in the pvh or the lower centers in the hindbrain and spinal cord . hardwired sympathetic outflow ( mainly by releasing norepinephrine ) is greater than that stimulated by epinephrine released by the adrenal medulla . loss of autonomic control from the pvh [ for instance by lesion of the nuclei ( foster et al . , 2010 ) ] can increase the accumulation of lipids in wat without influencing lipid mobilization . this indicates that obesity could be caused by excess energy deposition owing to malfunction of the sympathetic autonomic nervous system . although the cns as a whole has been well studied with respect to its role in detecting and integrating metabolic signals , the roles of specific cell types , such as astrocytes , have not . astrocytes are a major class of macroglial cells that occupy up to 50% of the total brain volume . beyond their classical roles in neuronal proliferation and differentiation , modulation of synaptic efficacy , and maintenance of ionic and neurotransmitter homeostasis , astrocytes also express adipokine receptors , including leptin receptors ( pan et al . , 2008 ) . thus , a defect in adipokine signals to the brain would affect both neurons and astrocytes . for example , in response to a high - fat diet , astrocytes display increased expression of leptin receptors ( hsuchou et al . , 2009 ) . in addition , a high - fat diet induces astrocytosis , causing an increase in astrocytic components between the blood vessels and the anorexigenic proopiomelanocortin ( pomc ) neurons in the arc of the mediobasal hypothalamus ( horvath et al . , 2010 ) . notably , leptin s role in directing the inhibition of food intake occurs in part through signaling in pomc neurons ( seeley et al . , 1997 ) . in obesity , although leptin concentration is increased in the circulation ( hyperleptinemia ) , the reactive astrocytes with their enlarged ensheathments hamper the pomc neurons ability to sense leptin in blood vessels , which might contribute to leptin resistance . in addition to astrocytes , another important non - neuronal cell type involved in metabolic sensing is the tanycyte , which resides along the wall of the third ventricle . owing to their expression of glucose transporter 2 ( garca et al . , 2003 ) , tanycytes are thought to be involved in glucosensing from the cerebral spinal fluid in the brain ventricle system . for accurate and timely monitoring of the peripheral metabolic state , certain areas are developed by the brain to more directly sense the metabolic feedback from the energy input site ( the gastrointestinal system ) and the energy storing site ( wat ) . these short - term and long - term inputs are integrated at different levels within the cns , and are incorporated into neuroendocrine and autonomic outputs to balance energy intake and expenditure . a malfunction at any level in this input - output circuit could contribute to a homeostasic imbalance and contribute to metabolic disorders . recent progress has been made in the treatment of metabolic syndrome through a combinational strategy , integrating different gut hormones and/or adipokines , while eliminating their potential side effects ( day et al . , 2009 ) . however , there are still many unknowns that make therapeutic strategies problematic . for example , before we completely understand the mechanism of leptin resistance ( for which cell specificity and intracellular signaling have yet to be clarified ) , leptin can not be used to treat obesity . another important unanswered question is how we can target the autonomic system to modulate energy homeostasis . in the past , efforts have been made to determine whether there are specific circuits between autonomic neurons and peripheral organs and tissues . for instance , are the liver and pancreas controlled by the same or different groups of pre - sympathetic neurons ( kreier et al . , 2006 ) ? are there neurochemical characteristics specific to each subtype of pre - autonomic neuron that enable their connections to peripheral organs or tissues ( bartness et al . is it possible to target specific subtypes of pre - autonomic neurons to manipulate their output to specific peripheral organs or tissues ? improved neuroanatomical and neurophysiological methods , combined with genetic tools , will be helpful in addressing these questions and will improve the outlook for anti - obesity therapy .