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Biomedical subjects

Susan F Akana

Publications and source records attributed to Susan F Akana.

12 recordsLinked to original sources
PubMed2006

Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage.

In the central nervous system, steroidogenic factor 1 (SF-1) is required for terminal differentiation of neurons within the ventromedial hypothalamus (VMH). Given the importance of this brain region in regulating physiological homeostasis including energy balance, we asked how sf-1 gene dosage affects VMH function. Despite an apparent normal VMH cytoarchitecture, sf-1 heterozygous (+/-) mice exhibited diet-induced obesity when they were group housed with hyperphagia and impaired sympathetic activity. On the basis of previous findings suggesting brain-derived neurotrophic factor (bdnf) as an SF-1 target gene, we assessed the colocalization of SF-1 and BDNF expressing neurons, as well as expression of the four exon-specific bdnf promoter transcripts in the VMH. Indeed, a subset of neurons located primarily in the ventrolateral VMH coexpress SF-1 and BDNF, and in contrast to other brain regions, bdnf I, II, and IV but not III are found. Consistent with these findings, cellular assays showed that SF-1 is able to activate exon I and IV promoters. More important, levels of bdnf I and IV in the VMH were reduced in heterozygous mice similar to levels observed in fasted wild-type mice. Collectively, we propose that a reduction in the sf-1 gene dosage directly affects BDNF levels in the VMH and disrupts normal hypothalamic function.

Animals↗
PubMed2006

From Malthus to motive: how the HPA axis engineers the phenotype, yoking needs to wants.

The hypothalamo-pituitary-adrenal (HPA) axis is the critical mediator of the vertebrate stress response system, responding to environmental stressors by maintaining internal homeostasis and coupling the needs of the body to the wants of the mind. The HPA axis has numerous complex drivers and highly flexible operating characterisitics. Major drivers include two circadian drivers, two extra-hypothalamic networks controlling top-down (psychogenic) and bottom-up (systemic) threats, and two intra-hypothalamic networks coordinating behavioral, autonomic, and neuroendocrine outflows. These various networks jointly and flexibly control HPA axis output of periodic (oscillatory) functions and a range of adventitious systemic or psychological threats, including predictable daily cycles of energy flow, actual metabolic deficits over many time scales, predicted metabolic deficits, and the state-dependent management of post-prandial responses to feeding. Evidence is provided that reparation of metabolic derangement by either food or glucocorticoids results in a metabolic signal that inhibits HPA activity. In short, the HPA axis is intimately involved in managing and remodeling peripheral energy fluxes, which appear to provide an unidentified metabolic inhibitory feedback signal to the HPA axis via glucocorticoids. In a complementary and perhaps a less appreciated role, adrenocortical hormones also act on brain to provide not only feedback, but feedforward control over the HPA axis itself and its various drivers, as well as coordinating behavioral and autonomic outflows, and mounting central incentive and memorial networks that are adaptive in both appetitive and aversive motivational modes. By centrally remodeling the phenotype, the HPA axis provides ballistic and predictive control over motor outflows relevant to the type of stressor. Evidence is examined concerning the global hypothesis that the HPA axis comprehensively induces integrative phenotypic plasticity, thus remodeling the body and its governor, the brain, to yoke the needs of the body to the wants of the mind. Adverse side effects of this yoking under conditions of glucocorticoid excess are discussed.

Animals↗
PubMed2006

Comparison of superior mesenteric versus jugular venous infusions of insulin in streptozotocin-diabetic rats on the choice of caloric intake, body weight, and fat stores.

Corticosterone (B) increases and insulin decreases food intake. However, in streptozotocin (STZ)-diabetic rats with high B, low insulin replacement promotes lard intake. To test the role of the liver on this, rats were given STZ and infused with insulin or vehicle into either the superior mesenteric or right jugular vein. Controls were nondiabetic; all rats were treated with high B. After 5 d, all rats were offered lard, 32% sucrose, chow, and water ad libitum until d 10. Diabetes exacerbated body weight loss from high B; this was prevented by insulin into the jugular, but not superior mesenteric, vein. Without insulin, STZ groups essentially consumed only chow; controls increased caloric intake about equally from the three sources. Insulin into both sites reduced chow and increased lard intake. Although circulating insulin was increased only by jugular infusion, plasma glucose and liver glycogen were similar after insulin into both sites. Fat depot weights differed: sc fat was heavier after jugular and mesenteric fat was heavier after mesenteric insulin infusions. We conclude that there are important site-specific effects of insulin in regulating the choice of, but not total, caloric intake, body weight, and fat storage in diabetic rats with high B. Furthermore, lard intake might be regulated by an insulin-derived, liver-mediated signal because superior mesenteric insulin infusion had similar effects on lard intake to jugular infusion but did not result in elevated circulating insulin levels likely associated with liver insulin removal.

Adipose Tissue↗
PubMed2006

Glucocorticoids, chronic stress, and obesity.

Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a chronic stressor, the steroids act in brain in a feed-forward fashion to recruit a stress-response network that biases ongoing autonomic, neuroendocrine, and behavioral outflow as well as responses to novel stressors. We review evidence for the role of glucocorticoids in activating the central stress-response network, and for mediation of this network by corticotropin-releasing factor (CRF). We briefly review the effects of CRF and its receptor antagonists on motor outflows in rodents, and examine the effects of glucocorticoids and CRF on monoaminergic neurons in brain. Corticosteroids stimulate behaviors that are mediated by dopaminergic mesolimbic "reward" pathways, and increase palatable feeding in rats. Moreover, in the absence of corticosteroids, the typical deficits in adrenalectomized rats are normalized by providing sucrose solutions to drink, suggesting that there is, in addition to the feed-forward action of glucocorticoids on brain, also a feedback action that is based on metabolic well being. Finally, we briefly discuss the problems with this network that normally serves to aid in responses to chronic stress, in our current overindulged, and underexercised society.

Animals↗
PubMed2004

Minireview: glucocorticoids--food intake, abdominal obesity, and wealthy nations in 2004.

Glucocorticoids have a major effect on food intake that is underappreciated, although the effects of glucocorticoids on metabolism and abdominal obesity are quite well understood. Physiologically appropriate concentrations of naturally secreted corticosteroids (cortisol in humans, corticosterone in rats) have major stimulatory effects on caloric intake and, in the presence of insulin, preference. We first address the close relationship between glucocorticoids and energy balance under both normal and abnormal conditions. Because excess caloric intake is stored in different fat depots, we also address the systemic effects of glucocorticoids on redistribution of stored energy preponderantly into intraabdominal fat depots. We provide strong evidence that glucocorticoids modify feeding and then discuss the role of insulin on the choice of ingested calories, as well as suggesting some central neural pathways that may be involved in these actions of glucocorticoids and insulin. Finally, we discuss the evolutionary utility of these actions of the stress hormones, and how dysregulatory effects of chronically elevated glucocorticoids may occur in our modern, rich societies.

Abdomen↗
PubMed2004

Interaction between corticosterone and insulin in obesity: regulation of lard intake and fat stores.

Passive elevations in glucocorticoids result in increased insulin and abdominal obesity with peripheral wasting, as observed in Cushing's syndrome, with little effect on chow intake. In the absence of insulin (streptozotocin-induced diabetes) diabetic rats markedly increase their chow intake in proportion to glucocorticoids. Given a choice of lard or chow, diabetic rats first eat lard, then reduce caloric intake to normal for 48 h before returning to hyperphagia on chow alone. We performed three experiments to determine the relationship of corticosterone and insulin to lard intake, chow intake, body weight, hormones, and fat depots. The results of these studies clarify the actions of both circulating glucocorticoids and insulin on caloric intake in adult male rats. Our experiments show that glucocorticoids provoke dose-related increases in total caloric intake that persist for days and weeks; the results also suggest that increasing insulin concentrations stimulated by glucocorticoids determine the amount of fat intake. Furthermore, we show that lard intake is associated with increasing insulin concentrations. Additionally, the results in adrenalectomized and adrenalectomized, streptozotocin-induced diabetic rats strongly suggest that it is a combination of corticosterone and insulin that increases abdominal fat depot weight. Independently of the hormonally manipulated rats, the results also show that intact rats voluntarily eat a considerable and stable proportion of their daily calories as lard when given a choice between lard and chow. These results suggest that some human obesities may result from elevated glucocorticoids and insulin increasing the proportional intake of high density calories.

Adipose Tissue↗
PubMed2003

Glucocorticoids act in the dorsal hindbrain to increase arterial pressure.

Glucocorticoid receptors (GRs) are present at a high density in the nucleus of the solitary tract (NTS), an area of the dorsal hindbrain (DHB) that is critical for blood pressure regulation. However, whether these receptors play any role in the regulation of blood pressure is unknown. We tested the hypothesis that glucocorticoids act in the DHB to increase arterial pressure using two experimental strategies. In one approach, we implanted pellets of corticosterone (Cort) or sham pellets onto the DHB over the NTS. Compared with rats with sham pellets, rats with DHB Cort pellets had an increased (P < 0.05) mean arterial pressure (111 +/- 2 vs. 104 +/- 1 mmHg) and heart rate (355 +/- 9 vs. 326 +/- 5 beats/min) after 4 days. In the second approach, we implanted subcutaneous Cort pellets to increase the systemic Cort concentration and then subsequently implanted pellets of the GR antagonist mifepristone (Mif; previously RU-38486) or sham pellets onto the DHB. Two days of DHB Mif treatment reduced (P < 0.05) mean arterial pressure in those rats with elevated plasma Cort levels (118 +/- 2 vs. 108 +/- 1 mmHg for sham vs. Mif DHB pellets). Cort and Mif pellets placed on the dura had no effects on arterial pressure or heart rate, ruling out systemic cardiovascular effects of the steroids. DHB Cort treatment had no effects on plasma Cort concentration or adrenal weight, indicating that the contents of the DHB Cort pellet did not diffuse into the systemic circulation or into the forebrain areas that regulate plasma Cort concentration in concentrations sufficient to produce physiological effects. Immunohistochemistry for the occupied GRs demonstrated that the Cort and Mif from the DHB pellets were delivered to the DHB with minimal diffusion to the ventral hindbrain or forebrain. We conclude that glucocorticoids act in the DHB to increase arterial pressure.

Adrenal Glands↗
PubMed2003

Chronic stress and obesity: a new view of "comfort food".

The effects of adrenal corticosteroids on subsequent adrenocorticotropin secretion are complex. Acutely (within hours), glucocorticoids (GCs) directly inhibit further activity in the hypothalamo-pituitary-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.

Adrenal Glands↗
PubMed2003

Compulsive behavior in the 5-HT2C receptor knockout mouse.

The efficacy of serotonergic pharmacotherapy indicates that serotonin (5-HT) plays a role in the treatment, if not the etiology, of obsessive-compulsive disorder (OCD). While some clinical evidence implicates 5-HT(2C) receptors in this disorder, a definitive function has yet to be validated. We hypothesized that 5-HT(2C) receptor knockout (KO) mice may display compulsive-like behavior. This paper describes characterization of several distinct, highly organized behaviors in mice lacking functional 5-HT(2C) receptors, which supports a compulsive-like syndrome.Compulsive-like behavior was assessed in male 5-HT(2C) receptor KO and wildtype (WT) mice. Chewing of non-nutritive clay, chewing patterns on plastic-mesh screens, and the frequency of head dipping were measured. 5-HT(2C) receptor KO mice chewed more clay, produced a distinct pattern of "neat" chewing of plastic screens and exhibited reduced habituation of head dipping activity compared to WT mice. We conclude that the 5-HT(2C) receptor null mutant mouse provides a promising model of compulsive behavior and a means to further explore the role of 5-HT in OCD.

Animals↗
PubMed2003

Repeated stress in young and old 5-HT(2C) receptor knockout mice.

Serotonin (5-HT)(2C) receptor null mutant (knockout, KO) mice develop hyperphagia and midlife obesity. Based upon previous observations indicating altered responsiveness to stressful environmental conditions in these mice, we hypothesized that this KO mouse was hyperresponsive to repeated stress. To test this, we examined the effect of two intensities of repeated stress on food intake and body weight in 5-HT(2C) receptor KO and wild-type (WT) mice. The stressors involved daily cage change (including handling) for 3 days then daily restraint for 4 days. On the final day, mice were immediately decapitated after restraint to assess levels of plasma hormones. Two ages were used: young (12 weeks) and old (32-34 weeks). Basally, young KO were prehyperphagic and weighed the same as WT. In the old mice, KO were frankly hyperphagic and heavier than WT. In response to repeated cage change alone, the genotype-specific difference in food intake in the young group was enhanced, whereas in the old group it was diminished. This stressor did not significantly affect body weight change or caloric efficiency with respect to age or genotype. Repeated restraint had little effect on the young mice. However, in the old mice, KO had decreases in relative body weight and caloric efficiency compared with WT. In the old KO mice, adrenocorticotrophic hormone (ACTH), corticosterone and insulin were increased compared with WT mice. Together, these findings indicate that 5-HT(2C) receptor KO mice are hyperresponsive to repeated stress and this effect is influenced by stressor intensity and initial metabolic state of the mouse.

Adrenocorticotropic Hormone↗
PubMed2003

A spoonful of sugar: feedback signals of energy stores and corticosterone regulate responses to chronic stress.

To begin to understand the effects of chronic stress on food intake and energy stores, the effects of increased activity in the hypothalamo-pituitary-adrenal (HPA) axis and glucocorticoids (GCs) on the body and brain must first be understood. We propose two major systems that are both GC sensitive: a metabolic feedback that is inhibitory and a direct central GC drive. Under basal conditions, the metabolic feedback signal to brain is dominant, although infusion of GC into a lateral brain ventricle blocks the effects of the metabolic feedback. Chronic stress activates GC secretion and brain nuclear GC receptor occupancy, markedly changing the normal relationships between these two major corticosteroid-activated systems. The stressor-induced switch in the relative strengths of these signals determines subsequent brain regulation of stress responses (behavioral, neuroendocrine and autonomic outflows). The metabolic feedback effects of GCs are mimicked by voluntary sucrose ingestion in adrenalectomized rats, and experiments suggest that the metabolic feedback also inhibits the stressor-induced direct GC drive on brain. We speculate that the interaction between peripheral and central GC-sensitive signaling systems may be coupled through the inhibitory actions of endogenous opiatergic inputs on corticotropin-releasing factor (CRF) neurons.

Adrenalectomy↗