The early life environment experienced by an individual in utero and during the neonatal period is a major factor in shaping later life disease risk-including susceptibility to develop obesity, ...diabetes, and cardiovascular disease. The incidence of metabolic disease is different between males and females. How the early life environment may underlie these sex differences is an area of active investigation.
The purpose of this review is to summarize our current understanding of how the early life environment influences metabolic disease risk in a sex specific manner. We also discuss the possible mechanisms responsible for mediating these sexually dimorphic effects and highlight the results of recent intervention studies in animal models.
Exposure to states of both under- and over-nutrition during early life predisposes both sexes to develop metabolic disease. Females seem particularly susceptible to develop increased adiposity and disrupted glucose homeostasis as a result of exposure to in utero undernutrition or high sugar environments, respectively. The male placenta is particularly vulnerable to damage by adverse nutritional states and this may underlie some of the metabolic phenotypes observed in adulthood. More studies investigating both sexes are needed to understand how changes to the early life environment impact differently on the long-term health of male and female individuals.
The trade-off between reward and effort is at the heart of most behavioral theories, from ecology to economics. Compared to reward, however, effort remains poorly understood, both at the behavioral ...and neurophysiological levels. This is important because unwillingness to overcome effort to gain reward is a common feature of many neuropsychiatric and neurological disorders. A recent surge in interest in the neurobiological basis of effort has led to seemingly conflicting results regarding the role of dopamine. We argue here that, upon closer examination, there is actually striking consensus across studies: dopamine primarily codes for future reward but is less sensitive to anticipated effort cost. This strong association between dopamine and the incentive effects of rewards places dopamine in a key position to promote reward-directed action.
Compared to reward, effort remains poorly understood, both at the behavioral and neurophysiological levels.
Dopamine has been proposed as central to effort-related decision making, but its role is not clearly defined.
In fact, the activity of midbrain dopamine neurons and mesolimbic dopamine levels are consistently modulated by anticipated future reward more strongly and consistently than effort, even when the weight of reward and effort on behavior are equated.
These signals may promote decisions to act based on the potential gain from a future reward.
The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin (POMC), melanocortin ...receptors (MC4Rs), and the endogenous antagonist agouti-related peptide (AgRP). Pomc and Mc4r deficiency in rodents and humans causes early onset of obesity, whereas a loss of Agrp function is associated with leanness. Accumulating evidence shows that many chronic diseases, including obesity, might originate during early life. The melanocortin system develops during a relatively long period beginning during embryonic life with the birth of POMC and AgRP neurons and continuing postnatally with the assembly of their neuronal circuitry. The development of the melanocortin system requires the tight temporal regulation of molecular factors, such as transcription factors and axon guidance molecules, and cellular mechanisms, such as autophagy. It also involves a complex interplay of endocrine and nutritional factors. The disruption of one or more of these developmental factors can lead to abnormal maturation and function of the melanocortin system and has profound metabolic consequences later in life.
Leptin secreted by adipocytes acts on the brain to reduce food intake by regulating neuronal activity in the mediobasal hypothalamus (MBH). Obesity is associated with resistance to high circulating ...leptin levels. Here, we demonstrate that peripherally administered leptin activates its receptor (LepR) in median eminence tanycytes followed by MBH neurons, a process requiring tanycytic ERK signaling and the passage of leptin through the cerebrospinal fluid. In mice lacking the signal-transducing LepRb isoform or with diet-induced obesity, leptin taken up by tanycytes accumulates in the median eminence and fails to reach the MBH. Triggering ERK signaling in tanycytes with EGF reestablishes leptin transport, elicits MBH neuron activation and energy expenditure in obese animals, and accelerates the restoration of leptin sensitivity upon the return to a normal-fat diet. ERK-dependent leptin transport by tanycytes could thus play a critical role in the pathophysiology of leptin resistance, and holds therapeutic potential for treating obesity.
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•Blood-borne leptin enters the hypothalamus through the median eminence•Tanycytes act as a checkpoint in the entry of leptin into the brain•LepRb-ERK signaling is required for hypothalamic leptin uptake•Triggering ERK signaling in tanycytes rescues leptin function in obese mice
Balland et al. show that ERK-dependent leptin transport by tancytes acts as a checkpoint for leptin’s access to the mediobasal hypothalamus. This transport is altered in mice with diet-induced obesity, which is restored by pharmacological activation of ERK signaling in tanycytes, leading to improved leptin sensitivity in obese mice.
The delivery of blood-borne molecules conveying metabolic information to neural networks that regulate energy homeostasis is restricted by brain barriers. The fenestrated endothelium of median ...eminence microvessels and tight junctions between tanycytes together compose one of these. Here, we show that the decrease in blood glucose levels during fasting alters the structural organization of this blood-hypothalamus barrier, resulting in the improved access of metabolic substrates to the arcuate nucleus. These changes are mimicked by 2-deoxyglucose-induced glucoprivation and reversed by raising blood glucose levels after fasting. Furthermore, we show that VEGF-A expression in tanycytes modulates these barrier properties. The neutralization of VEGF signaling blocks fasting-induced barrier remodeling and significantly impairs the physiological response to refeeding. These results implicate glucose in the control of blood-hypothalamus exchanges through a VEGF-dependent mechanism and demonstrate a hitherto unappreciated role for tanycytes and the permeable microvessels associated with them in the adaptive metabolic response to fasting.
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► Fasting induces the plasticity of brain barriers in hypothalamic feeding regions ► Central neuroglucopenia triggers blood-hypothalamus barrier plasticity ► Fasting-induced brain barrier plasticity requires VEGF-A expression in tanycytes ► The tanycytic barrier modulates blood-borne signals access to CNS feeding circuits
The hypothalamus is a large brain region made of nuclei and areas involved in the control of behaviors and physiological regulations. Among them, the arcuate nucleus (ARH) and the lateral ...hypothalamic area (LHA) contain key neuronal populations expressing the pro-opiomelanocortin (POMC), the agouti-related peptide (AgRP), and the melanin-concentrating hormone (MCH), respectively, that are involved in goal-oriented behaviors (such as feeding behavior) and glucose homeostasis. These neuronal populations are generated from distinct parts of the germinative neuroepithelium during embryonic life, and acquire their cell fate under the influence of morphogen proteins, specific transcription factors, and epigenetic modulators. POMC and MCH neuronal development continues by sending long descending axonal projections before birth under the control of axon guidance molecules such as Netrin1 and Slit2. Later, during the postnatal period, POMC and AgRP neurons develop intra-hypothalamic projections notably to the paraventricular nucleus of the hypothalamus through the influence of other axon guidance cues such as the class3 Semaphorins. Other cellular processes, such as autophagy and primary cilia function, and hormonal cues also appear critical for the proper development of POMC neurons.
•POMC/AgRP and MCH neurons are born during embryonic life.•Transcription factors, morphogen proteins, and epigenetic modulators control POMC/AgRP and MCH neurons differentiation.•POMC/AgRP and MCH wiring occurs pre- and post-natally.•Cellular processes such as autophagy and primary cilia play a critical role in POMC neurons wiring.
Abstract Leptin is well known as an important hormone in the central control of feeding behavior. During development, fetuses and newborns are exposed to leptin and recent evidence has shown that ...leptin receptors are widespread throughout the developing brain. Accordingly, leptin affects brain development during both pre- and postnatal life. The actions of leptin in the developing brain are generally permanent and range from the establishment of hypothalamic circuits to plasticity in cortical pathways. The cellular events mediated by leptin include the following: neurogenesis, axon growth, and synaptogenesis. Nutritional manipulation of leptin secretion during perinatal life has generated considerable concern, and the developing brain appears to be a particularly sensitive target for these environmental changes.
The brain stem noradrenergic nucleus locus coeruleus (LC) is involved in various costly processes: arousal, stress, and attention. Recent work has pointed toward an implication in physical effort, ...and indirect evidence suggests that the LC could be also involved in cognitive effort. To assess the dynamic relation between LC activity, effort production, and difficulty, we recorded the activity of 193 LC single units in 5 monkeys performing 2 discounting tasks (a delay discounting task and a force discounting task), as well as a simpler target detection task where conditions were matched for difficulty and only differed in terms of sensory-motor processes. First, LC neurons displayed a transient activation both when monkeys initiated an action and when exerting force. Second, the magnitude of the activation scaled with the associated difficulty, and, potentially, the corresponding amount of effort produced, both for decision and force production. Indeed, at action initiation in both discounting tasks, LC activation increased in conditions associated with lower average engagement rate, i.e., those requiring more cognitive control to trigger the response. Decision-related activation also scaled with response time (RT), over and above task parameters, in line with the idea that it reflects the amount of resources (here time) spent on the decision process. During force production, LC activation only scaled with the amount of force produced in the force discounting task, but not in the control target detection task, where subjective difficulty was equivalent across conditions. Our data show that LC neurons dynamically track the amount of effort produced to face both cognitive and physical challenges with a subsecond precision. This works provides key insight into effort processing and the contribution of the noradrenergic system, which is affected in several pathologies where effort is impaired, including Parkinson disease and depression.
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