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Biomedical subjects

Mary F Dallman

Publications and source records attributed to Mary F Dallman.

At least 19 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

Diverse basal and stress-related phenotypes of Sprague Dawley rats from three vendors.

Based on observed phenotypic differences in growth and ACTH responses to stress in Sprague Dawley rats obtained from different vendors, we ran head-to-head comparisons on rats obtained from three different vendors, Harlan, Charles River, and Simonsen, with respect to baseline phenotypic differences and a metabolic feedback hypothesis of hypothalamo-pituitary-adrenal (HPA) regulation. Charles River and Harlan rats gained weight faster than Simonsen rats, but chow intake standardized for body weight was not increased, consistent with their greater caloric efficiency. Weight gain was inversely related with mean daily temperatures, without differences in activity levels. Half of the animals given lard and 32% sucrose solutions in addition to chow increased caloric intake and core temperature, decreased caloric efficiency, and increased fat depots, leptin, and in Simonsen rats, insulin. A 5-day regimen of once-daily 2-h restraint decreased feeding and caloric efficiency. Rats from two vendors with the availability of sucrose and lard, Charles River and Simonsen, showed blunted HPA responses to restraint compared to chow controls, whereas the Harlans exhibited no adrenocorticotropin (ACTH) response and an amplified adrenocortical response on the high-energy diet compared to chow controls. Substantial phenotypic differences exist between Sprague Dawley rats from different vendors with respect to metabolism and HPA function. The metabolic feedback hypothesis was supported in two of the three vendors' rats.

Adrenocorticotropic Hormone↗
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↗
PubMed2005

Fast glucocorticoid actions on brain: back to the future.

Rapid, non-transcriptionally mediated, effects of glucocorticoids affect many behaviors as well as inhibition of function in the hypothalamo-pituitary-adrenal axis. In this short review, it is argued that the fast glucocorticoid actions which are mediated by membrane receptors are an ancient type of sterol/steroid-mediated effect, and that these may be the primordial glucocorticoid receptors. Although the fast feedback actions of the glucocorticoids enjoyed study in the middle of the last century, new results and the availability of new techniques suggest that it is again time for a concerted effort to be made to understand the mechanism(s) of these rapid effects.

Animals↗
PubMed2005

Decreased gonadotropin-releasing hormone neuronal activity is associated with decreased fertility and dysregulation of food intake in the female GPR-4 transgenic rat.

Expression of a cAMP-specific phosphodiesterase in GnRH neurons in the GPR-4 transgenic rat resulted in decreased LH levels and pulse frequency and diminished fertility. We have characterized changes in fertility, adiposity, and reproductive and metabolic hormones with age. Although LH levels were decreased in 3-, 6-, and 9-month-old GPR-4 females relative to wild-type (WT) controls, GPR-4 females did not become anovulatory until 6 months of age. No differences were observed in FSH, estradiol, or androstenedione levels in 3-, 6-, or 9-month-old GPR-4 and WT females. At 9 months of age, GPR-4 females had significantly increased abdominal and sc fat depot weights that were associated with increased leptin and insulin levels not observed in WT females. We tested the hypothesis that metabolic changes observed at 9 months of age were the result of dysregulation of the mechanisms controlling energy balance. Two-month-old female GPR-4 rats placed on a high-energy diet gained weight at a rate significantly greater than WT females and, after 24 d, developed the same metabolic phenotype observed in 9-month-old GRP-4 females (increased abdominal and sc fat associated with elevated leptin and insulin concentrations). Overeating did not correlate with changes in estradiol or androstenedione levels. We conclude that decreased GnRH neuronal activity is closely associated with decreased reproductive function and dysregulation of food intake.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Choice of lard, but not total lard calories, damps adrenocorticotropin responses to restraint.

Although rats given the choice of eating high-density calories as concentrated sucrose solutions or lard exhibit reduced responsivity in the hypothalamo-pituitary-adrenal axis, rats fed high-fat diets have normal or augmented responses to stressors. To resolve this apparent discrepancy, we compared in adult male rats the effects of 7-d feeding with lard + chow (choice) to feeding a 50% lard-chow mixture (no-choice) and to chow only. Rats with choice composed diets with 50-60% total calories from lard. Rats were exposed to 30 min of restraint on d 7. In the choice group, there was a robust inhibition of ACTH and corticosterone responses to restraint compared with chow or no-choice groups. Total caloric intake was less with choice than no-choice. Fat depot weights and body weight gain were similar in the high-fat groups. Leptin concentrations were equal but insulin was higher in the choice group. We conclude the following: 1) choice of eating high-density calories strongly damps hypothalamo-pituitary-adrenal responses to stress; without choice, high-density diet is ineffective; and 2) insulin may signal metabolic well-being, and may act through hypothalamic sites to reduce caloric intake but through forebrain sites to damp stress responses.

Adrenal Glands↗
PubMed2005

Chronic stress and comfort foods: self-medication and abdominal obesity.

Central corticotropin-releasing factor (CRF) networks are recruited by chronic stressors and elevated glucocorticoids (GCs) that initiate recruitment of central CRF activity in the amygdala. Increased central activity of the CRF network stimulates all monoaminergic cell groups, as well as premotor autonomic and other limbic structures resulting in the typical arousal, behavioral changes, autonomic, and neuroendocrine changes that accompany the chronic imposition of a stressor. By contrast, elevated GCs appear, through a variety of means to counteract the effects of central CRF, which they have initiated. Together with insulin, the GCs stimulate drive for and ingestion of "comfort foods" that may directly result in reduction of the negative effects of the chronic stressor in the nucleus Accumbens, through stimulation of the anterior, more pleasure-associated part of this cell group, thus reducing the weight of the stress-stimulated posterior, more defensive part. Furthermore, the shift in caloric intake from chow to preference for "comfort foods," together with elevated GCs and insulin, reorganize energy stores from a peripheral to a central distribution, primarily as abdominal fat. A signal associated with this fat depot appears, as with eating "comfort foods," to reduce the influence of the chronic stress network on behaviors, autonomic, and neuroendocrine outflow.

Animals↗
PubMed2005

Single, but not multiple pairings of sucrose and corticosterone enhance memory for sucrose drinking and amplify remote reward relativity effects.

This study tested whether pre-training pairings of ingestion of a 32% sucrose solution and injection(s) of corticosterone (B) would enhance later ingestion in the absence of B, and whether these effects would carry over into later contrast-like effects when animals were subsequently shifted to 4% sucrose. Frequency-dependence of these pairings was also examined. Three groups of male Sprague-Dawley rats were adrenalectomized (ADX). A fourth group was sham ADX. Each ADX group received three presentations of sucrose and B (666 microg/kg, s.c.). One received unpaired presentations (separated by days), one received two unpaired presentations and one paired (i.e., simultaneous) presentation, and one received three paired presentations. Shams received three sucrose presentations paired with saline. Single, but not multiple pairings of B with ingestion of a 32% sucrose solution enhanced later sucrose ingestion, a memorial-like effect that carried over into later, opposite contrast-like effects upon presentation of a less-preferred 4% sucrose solution. These effects could not be easily ascribed to differences in training, other than the pairing regimen itself, nor to motivational differences at the time of testing, and were presumed to be memorial. The pairing and frequency-dependence of these appetitive phenomena are analogous to what is frequently observed during acute or chronic exposure to aversive situations and/or neuromodulatory stress hormones, in terms of their bidirectional effects on memory. Through effects on memory, stress hormones may modulate reward and reward relativity.

Adrenalectomy↗
PubMed2005

Glucocorticoids dose-dependently remodel energy stores and amplify incentive relativity effects.

To test whether glucocorticoids amplify incentive motivation, three groups of rats were adrenalectomized and replaced subcutaneously with pellets of corticosterone (B), containing 0, 30, or 80% B and cholesterol. A fourth group of sham adrenalectomized rats received cholesterol pellets. Animals were placed on a four-arm maze baited with 32% sucrose for 5-min daily sessions. After 7 days of minimal drinking on the maze at free-feeding weights, their body weights were gradually reduced to 90% of their free-feeding weights for the next 12 days (pre-shift phase). The sucrose concentration was reduced to 4% for the next 2 days (post-shift phase). B dose-dependently increased 32% sucrose intake, insulin secretion, and relative fat depots. Intake was reduced similarly in all groups following the shift to 4%, resulting in a relative B-dependent intake suppression following the shift to 4%. Videoscoring of locomotor activity indicated that search behaviors were not different between groups prior to the shift to 4%, whereas the increase in search behavior following the shift to 4% sucrose was entirely B-dependent. These data were predicted by a new model of chronic stress positing two regulatory axes on brain by glucocorticoids: one indirect axis by which glucocorticoids remodel energy stores to provide metabolic feedback and a direct axis whereby glucocorticoids act directly on brain to remodel appetitive structure.

Adaptation, Physiological↗
PubMed2005

c-Fos after incentive shifts: expectancy, incredulity, and recovery.

Rats were used in a successive negative contrast procedure to determine which brain structures were activated by sucrose concentration downshifts, and on what day this occurred. Subjects were given preshift solutions for 12 days before being shifted to their postshift concentrations. Groups included 2 unshifted controls (32%-32% and 4%-4%) and 1 shifted group (32%-4%). Half of each group was killed 1 hr after the first exposure to the shifted solution (Shift 1), and half after the second exposure (Shift 2). Brains were processed for c-Fos-like immunoreactivity (FLI). Two major patterns emerged. Terminal drinking of 32% sucrose activated minimal brainstem regions involved in palatable taste, visceral feedback, and fluid homeostasis. In contrast, shifted subjects showed extensive cortical activation with selective activation in cerebral nuclei and brainstem. Robust FLI on Shift 1 was absent on Shift 2, consistent with evidence for rapid (1-trial) changes in all major motor outputs mediated by expectancy.

Animals↗
PubMed2005

Hepatic vagotomy alters limbic and hypothalamic neuropeptide responses to insulin-dependent diabetes and voluntary lard ingestion.

Hypothalamic anorexigenic [corticotropin-releasing factor (CRF) and proopiomelanocortin] peptides decrease and the orexigen, neuropeptide Y, increases with diabetic hyperphagia. However, when diabetic rats are allowed to eat lard (saturated fat) as well as chow, both caloric intake and hypothalamic peptides normalize. These neuropeptide responses to lard require an intact hepatic vagus [la Fleur et al. (2003) Diabetes, 52, 2321-2330]. Here, we delineate temporal interactions after lard consumption +/- hepatic vagotomy (HV) between feeding and brain neuropeptide expression in insulin-dependent diabetic rats. CRF-mRNA was reduced in the paraventricular nuclei (PVN) by 6 h after presentation of lard, before caloric intake increased in HV-diabetic rats, and did not increase at 30 or 36 h, as it did in shamHV-diabetic rats eating lard. CRF-mRNA was increased in the bed nuclei of the stria terminalis of HV-diabetic rats compared with shamHV-diabetic rats only when caloric intake was high at 30 or 36 h. At 36 h, shamHV-diabetic rats eating chow had increased CRF-mRNA in the central amygdala but diabetic rats eating lard had decreased CRF-mRNA, whereas HV-diabetic rats eating chow or lard had normal CRF-mRNA in the central amygdala. We conclude that eating lard restores peptide expression to normal in the hypothalamus of diabetic rats, and because decreased CRF-mRNA in the PVN precedes the increase in caloric intake in HV-diabetic rats eating lard, that the loss of a hepatic vagal signal to PVN may be responsible for increased intake; moreover, CRF-mRNA in limbic structures is also sensitive to both HV and lard ingestion in diabetic rats.

Animals↗
PubMed2004

Time-dependent alterations in mRNA expression of brain neuropeptides regulating energy balance and hypothalamo-pituitary-adrenal activity after withdrawal from intermittent morphine treatment.

Chronic stressors alter brain function and may leave traces after their relief. We used intermittent morphine treatment to examine the relationships between stress-induced changes in energy balance and hypothalamo-pituitary-adrenal (HPA) activity and the recovery thereafter. We studied the effects of morphine injections on energy balance, hormones and fat stores, brain neuropeptide expression, and the ACTH and corticosterone responses to restraint 12 hr after the final injection and 8 d later during recovery. Weight gain, food intake, and caloric efficiency decreased at morphine onset, and these were maintained throughout the morphine injections. At 12 hr, fat stores, leptin, insulin, and testosterone concentrations were reduced. Subsequently, body weight gain and food intake increased and caloric efficiency was above control during the final days. By the eighth recovery day, fat stores and peripheral hormones were no longer depressed. At 12 hr, an over-response of CRF mRNA to restraint occurred in the hypothalamus, similar to the facilitated ACTH and corticosterone responses. On day 8, the hypothalamic CRF mRNA response to restraint was still facilitated, opposite to inhibited ACTH responses. Hypothalamic CRF mRNA correlated highly with mesenteric fat weight in morphine-treated rats. We conclude that there is a prolonged recovery from chronic stressors involving interrelated changes in energy balance and HPA activity. Nonetheless, 8 d after withdrawal from morphine, rats still display facilitated central stress responses, similar to the HPA symptoms described in posttraumatic stress disorder patients. Repeated partial withdrawal associated with intermittent morphine treatment, compounded by complete withdrawal associated with termination of the treatment, is likely required for these metabolic and HPA derangements.

Animals↗
PubMed2004

Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress.

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.

Adrenalectomy↗
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↗