The effects of adrenal corticosteroids on subsequent adrenocorticotropin secretion are complex. Acutely (within hours), glucocorticoids (GCs) directly inhibit further activity in the hypothalamopituitary-adrenal axis, but the chronic actions (across days) of these steroids on brain are directly excitatory. Chronically high concentrations of GCs act in three ways that are functionally congruent. (i) GCs increase the expression of corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala, a critical node in the emotional brain. CRF enables recruitment of a chronic stress-response network. (ii) GCs increase the salience of pleasurable or compulsive activities (ingesting sucrose, fat, and drugs, or wheel-running). This motivates ingestion of ''comfort food.'' (iii) GCs act systemically to increase abdominal fat depots. This allows an increased signal of abdominal energy stores to inhibit catecholamines in the brainstem and CRF expression in hypothalamic neurons regulating adrenocorticotropin. Chronic stress, together with high GC concentrations, usually decreases body weight gain in rats; by contrast, in stressed or depressed humans chronic stress induces either increased comfort food intake and body weight gain or decreased intake and body weight loss. Comfort food ingestion that produces abdominal obesity, decreases CRF mRNA in the hypothalamus of rats. Depressed people who overeat have decreased cerebrospinal CRF, catecholamine concentrations, and hypothalamo-pituitary-adrenal activity. We propose that people eat comfort food in an attempt to reduce the activity in the chronic stress-response network with its attendant anxiety. These mechanisms, determined in rats, may explain some of the epidemic of obesity occurring in our society.corticotropin-releasing factor ͉ glucocorticoids ͉ high fat ͉ sucrose ͉ motivation O ur understanding of regulation of function in the hypothalamo-pituitary-adrenal (HPA) axis has changed profoundly in the last decades. The discovery of functions of the distributed cell groups of corticotropin-releasing factor (CRF) neurons, the motor neurons for activation of the pituitary and adrenal, as well as the tight interrelationships between calories, body weight, energy stores, and the HPA axis have occasioned revisions in our thinking. The upshot is a new working model, the output of which is modifiable through manipulation of caloric input (Fig. 1). The long-term consequences of such output modification in chronically stressed individuals may include deleterious weight gain, abdominal obesity, type II diabetes, increased cardiovascular morbidity, and mortality. We arrived at this model through interpretation of the results from studies on manipulation of energy balance, central CRF, and the effects of acute and chronic stress and glucocorticoid (GC) treatment in intact and adrenalectomized rats. GC Effects on HPA Function: Acute and ChronicCanonical GC-feedback inhibition of subsequent adrenocorticotropin (ACTH) secretion is easily demonstrated acutely, within the fi...

Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.

Stress and emotional brain networks foster eating behaviors that may lead to obesity. The neural networks underlying the complex interactions among stressors, body, brain and food intake are now better understood. Stressors, by activating a neural stress-response network, bias cognition toward increased emotional activity and degraded executive function. This causes formed habits to be used rather than a cognitive appraisal of responses. Stress also induces secretion of both glucocorticoids, which increases motivation for food, and insulin, which promotes food intake and obesity. Pleasurable feeding then reduces activity in the stress-response network, reinforcing the feeding habit. These effects of stressors emphasize the importance of teaching mental reappraisal techniques to restore responses from habitual to thoughtful, thus battling stress-induced obesity.We find ourselves in the middle of a severe epidemic of obesity that affects not only adults but also has recently permeated younger generations [1][2][3][4][5][6]. An understanding of the underlying physiological causes of this growing problem is required for its solution.The physiology of feeding behavior has been studied for many years, generally providing rodents or other experimental animals with standard lab chow. These studies using a single bland food, perforce concentrated on the hypothalamic and brainstem regulation of energy balance. The emergence of leptin as a key fat hormone that stimulates secretion of the anorexigenic and sympathetic-stimulatory neuropeptides and inhibits secretion of the orexigenic and parasympathetic-stimulatory neuropeptides was of critical importance in understanding homeostatic regulation of energy balance [1,[7][8][9][10]. Moreover, findings about other hormonal signals that acutely affect feeding, such as ghrelin and other gut peptides activated by fasting or feeding, added to our knowledge about regulators of energy balance [9,10]. However, it has become glaringly obvious that voluntary behaviors, stimulated by external or internal challenges or pleasurable feelings, memories and habits can override the basic homeostatic controls of energy balance [11][12][13][14][15][16][17].The increased amount of perceived stress experienced by individuals in modern society affects feeding behavior [18][19][20]. In fact, a recent study showed that sadness favored eating of high fat/sweet, hedonically rewarding foods, whereas intake during a happy state favored dried fruit [21]. The basis for this behavior and others that lead to obesity are slowly becoming understood. They include cortical and subcortical pathways that involve learning and memory of reward and pleasure, as well as habit formation and decreased cognitive control. Elevated stress hormones and palatable food intake and the consequent accretion of fat may serve as feedback signals that reduce perceived stress [22], thus reinforcing stress-induced feeding behavior.

Corticosteroid feedback inhibits the brain-hypothalamo-pituitary units of the adrenocortical system. Naturally occurring corticosteroids may have their primary actions in vivo at brain and hypothalamic sites of feedback, whereas synthetic glucocorticoids that do not bind to transcortin may act primarily on corticotropes and regions of brain outside the blood-brain barrier. There appear to be three major time frames of corticosteroid action: fast, intermediate and slow. These time frames probably are the consequence of three separate mechanisms of corticosteroid action at feedback-sensitive sites. The rapidity of occurrence of fast feedback is not compatible with a nuclear site of corticosteroid action, and protein synthesis is not required. The action of CRF on ACTH release may be inhibited by a rapid effect of corticosteroids at the cell membrane. Since stimulated, but not basal, ACTH and CRF release are inhibited in vitro, the corticosteroids may inhibit some event in stimulus-secretion coupling (e.g., cAMP production). Intermediate feedback also decreases ACTH release in response to stimulation of the corticotrope, but does not affect ACTH synthesis; CRF synthesis and release both appear to be affected by the intermediate corticosteroid action. The mechanism of intermediate feedback requires the presence of a protein whose synthesis is corticosteroid-dependent; however, the role of this protein is unknown. Intermediate feedback, like fast feedback, apparently does not involve inhibition of total ACTH stores or the releasable pool of ACTH since basal secretion of ACTH is also not inhibited in vitro within this time domain. On the other hand, slow feedback apparently involves the classical genomic steroid mechanism of action; slow feedback reduces pituitary ACTH content by decreasing levels of mRNA encoding for POMC, the ACTH precursor molecule. Slow feedback, therefore, inhibits basal as well as stimulus induced ACTH secretion. Corticosteroid-induced inhibition of basal ACTH secretion has been shown to occur within 2 h in vivo but not in vitro. The time course and sensitivity of this feedback effect is different than that demonstrated for stimulus induced secretion. This difference suggests that basal secretion is activated by different pathways to (CRF and) ACTH secretion. There is some evidence that suggests that whereas comparator elements are not reset during stress, a comparator element is reset during the course of the circadian rhythm so that different basal levels of steroid are achieved.(ABSTRACT TRUNCATED AT 400 WORDS)

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We suggested a new model of the effects of glucocorticoids (GCs) exerted during chronic stress, in which GCs directly stimulate activities in the brain while indirectly inhibiting activity in the hypothalamo-pituitary-adrenal (HPA) axis through their metabolic shifts in energy stores in the periphery. This study is an initial test of our model. In a 2 x 2 design, we provided ad lib access to calorically dense lard and sucrose (comfort food) + chow or chow alone, and repeatedly restrained half of the rats in each group for 5 d (3 h/d). We measured caloric intake, body weight, caloric efficiency, ACTH, corticosterone (B), and testosterone during the period of restraint and leptin, insulin, and fat depot weights, as well as hypothalamic corticotropin-releasing factor mRNA at the end of the period. We hypothesized that chronically restrained rats would exhibit a relative increase in comfort food ingestion and that these rats would have reduced HPA responses to repeated restraint. Although total caloric intake was reduced in both groups of restrained rats, compared with controls, the proportion of comfort food ingested increased in the restrained rats compared with their nonrestrained controls. Moreover, caloric efficiency was rescued in the stressed, comfort food group. Furthermore, ACTH and B responses to the repeated restraint bouts were reduced in the rats with access to comfort food. Corticotropin-releasing factor mRNA was reduced in control rats eating comfort food compared with those eating chow, but there were no differences between the stressed groups. The results of this experiment tend to support our model of chronic effects of stress and GCs, showing a stressor-induced preference for comfort food, and a comfort-food reduction in activity of the HPA axis.

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