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1.
Behav Processes ; 165: 23-28, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31132444

ABSTRACT

Circadian rhythms organize behavior and physiological processes to be appropriate to the predictable cycle of daily events. These rhythms are entrained by stimuli that provide time of day cues (zeitgebers), such as light, which regulates the sleep-wake cycle and associated rhythms. But other events, including meals, social cues, and bouts of locomotor activity, can act as zeitgebers. Recent evidence shows that most organs and tissues contain cells that are capable of some degree of independent circadian cycling, suggesting the circadian system is broadly and diffusely distributed. Within laboratory studies of behavior, circadian rhythms tend to be treated as a complication to be minimized, but they offer a useful model of predictable shifts in behavioral tendencies. In the present review, we summarize the evidence that formed the basis for a hypothesis that drugs of abuse can entrain circadian rhythms and describe the outcome of a series of experiments designed to test that hypothesis. We propose that such drug-entrained rhythms may contribute to demonstrated daily variations in drug metabolism, tolerance, and sensitivity to drug reward. Of particular importance, these rhythms may be evoked by a single episode of drug taking, strengthen with repeated episodes, and re-emerge after long periods of abstinence, thereby contributing to drug abuse, addiction, and relapse.


Subject(s)
Circadian Rhythm/drug effects , Feeding Behavior/physiology , Illicit Drugs/pharmacology , Animals , Brain/physiopathology , Circadian Rhythm/physiology , Cues , Drug Tolerance , Habituation, Psychophysiologic/physiology , Humans , Illicit Drugs/pharmacokinetics , Metabolic Clearance Rate/physiology , Motivation/drug effects , Motivation/physiology , Substance-Related Disorders/physiopathology , Substance-Related Disorders/psychology
2.
Stress ; 13(3): 248-57, 2010 May.
Article in English | MEDLINE | ID: mdl-20392196

ABSTRACT

The hypothalamic-pituitary-adrenal (HPA) axis self-regulates through a glucocorticoid negative feedback mechanism that is stereotypically slow and long lasting. Rapid (seconds to minutes) glucocorticoid feedback, however, inhibits stress-induced adrenocorticotropic hormone (ACTH) secretion too quickly to result from classic transcriptional effects of the occupied glucocorticoid receptor. Cannabinoids may act as rapid intermediary messengers between glucocorticoids and HPA activation via retroactive inhibition of afferent glutamate stimulation of the corticotropin-releasing factor neurons in the paraventricular nucleus. We demonstrated fast feedback effects of GR stimulation and blockade and observed the effect of cannabinoid receptor (CB1) antagonist AM251 on HPA axis reactivity in vivo. Rats were injected intraperitoneally with varying doses of the specific GR agonist RU28362, the GR antagonist RU486, or AM251 2 min before restraint. Blood was collected at predetermined times and corticosterone and ACTH concentrations were measured. RU28362 blunted stress-induced ACTH secretion while RU486 and AM251 significantly increased stress-induced ACTH release 15 min after restraint onset. Next, we injected AM251 58 min before RU28362, 2 min before restraint, to determine if inhibition of ACTH by RU28362 was contingent on CB1 activation. Unexpectedly, CB1 blockade failed to prevent glucocorticoid negative feedback and instead enhanced it. These studies not only establish an in vivo fast feedback model but show that rapid glucococorticoid negative feedback is similarly altered by GR and CB1 blockade. Although the hormonal consequences of acute AM251 treatment were strikingly similar to those of RU486 treatment, we are unable to draw conclusions about the serial nature of the interaction between GR activation and CB release from these results.


Subject(s)
Cannabinoids/metabolism , Glucocorticoids/metabolism , Hypothalamo-Hypophyseal System/physiology , Pituitary-Adrenal System/physiology , Stress, Physiological/physiology , Adrenocorticotropic Hormone/metabolism , Androstanols/pharmacology , Animals , Dose-Response Relationship, Drug , Feedback, Physiological/drug effects , Feedback, Physiological/physiology , Hormone Antagonists/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/metabolism , Male , Mifepristone/pharmacology , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/metabolism , Piperidines/pharmacology , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/metabolism , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB2/metabolism , Receptors, Glutamate/metabolism , Restraint, Physical , Stress, Physiological/drug effects
3.
Am J Physiol Regul Integr Comp Physiol ; 296(5): R1366-75, 2009 May.
Article in English | MEDLINE | ID: mdl-19279289

ABSTRACT

Corticosterone and insulin play complex roles in the amount and composition of calories ingested, and the utilization and deposition of this energy. Understanding the interplay of these two hormones is complicated because increasing concentrations of corticosterone dose-dependently increase circulating insulin levels. We addressed individual contributions of each hormone by controlling, at steady-state levels, corticosterone (by adrenalectomy and exogenous replacement) and insulin (by streptozotocin-induced destruction of pancreatic beta-cells and exogenous replacement) across a spectrum of concentrations in rats, creating 8 hormonal combinations. For 5 days after surgery, all rats received chow. At day 5, they were subdivided into those that continued to receive chow and those that had a choice between chow, lard, and 32% sucrose for a further 5 days. During the choice/chow period, total calories ingested were stimulated by corticosterone and choice diet, and subject to a corticosterone-insulin interaction. Sucrose, but not lard, intake was stimulated by insulin. Body weight was increased by insulin, decreased by high corticosterone, and unaffected by diet. White adipose tissue depot weights were stimulated by insulin, corticosterone, and diet. Plasma triglycerides, free fatty acids, total ketone bodies, glucose, and glycerol were all significantly increased by corticosterone and the choice diet but inhibited by insulin. In contrast, plasma leptin was only increased by insulin and diet, plasma glucagon and liver glycogen was only affected by insulin and liver triglycerides, and arcuate nucleus proopiomelanocortin mRNA was only influenced by diet. Collectively, these data show that corticosterone and insulin determine the intake, form, and compartmentalization of energy both independently and interactively.


Subject(s)
Corticosterone/physiology , Energy Intake/physiology , Energy Metabolism/physiology , Insulin/physiology , Adrenalectomy , Animals , Arcuate Nucleus of Hypothalamus/metabolism , Body Weight/physiology , Diabetes Mellitus, Experimental/metabolism , Disease Models, Animal , Glycogen/metabolism , Leptin/metabolism , Liver/metabolism , Male , Neuropeptide Y/metabolism , Pro-Opiomelanocortin/metabolism , Rats , Rats, Sprague-Dawley , Streptozocin , Triglycerides/metabolism
4.
Ann Surg ; 249(2): 269-76, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19212181

ABSTRACT

OBJECTIVE: We sought to examine insulin-sensitive food intake behavior and neuroendocrine and metabolic variables of rats that had undergone a duodenal-jejunal bypass (DJB). SUMMARY OF BACKGROUND DATA: A DJB that circumvents the duodenum and proximal jejunum while leaving the stomach unperturbed rapidly improves insulin sensitivity in type 2 diabetic rats. This segment of proximal small intestine is innervated by the gastroduodenal branch of the vagus nerve, the transection of which influences food intake choices in streptozotocin-diabetic rats. METHODS: Rats were first placed on a choice of chow and lard for 7 days and additionally provided with an enriched liquid diet for another 7 days before surgery and were allowed only the liquid diet for 7 days after either a sham or DJB operation. RESULTS: After surgery, DJB-operated rats initially consumed less than the sham-operated counterparts. When the rats were subsequently provided with the choice of chow and lard for 7 days, there were no differences in intake between the DJB and sham-operated groups. Similarly, the majority of metabolic and neuroendocrine variables measured were unchanged. However, DJB-operated rats exhibited greater mesenteric white adipose tissue weight, fecal output, arcuate nucleus neuropeptide Y mRNA expression, plasma corticosterone, and glucagon levels together with reduced plasma leptin concentrations. CONCLUSIONS: DJB surgery does not produce significant differences in food intake choices after a period of recovery; however, there are enduring metabolic and neuroendocrine changes, which are collectively important to understanding the beneficial outcomes of the operation.


Subject(s)
Jejunoileal Bypass , Obesity, Morbid/metabolism , Obesity, Morbid/surgery , Animals , Disease Models, Animal , Eating , Insulin Resistance/physiology , Intestine, Small/metabolism , Intestine, Small/physiopathology , Male , Neurosecretory Systems/physiopathology , Postoperative Period , Rats , Rats, Sprague-Dawley
5.
Endocrinology ; 150(5): 2325-33, 2009 May.
Article in English | MEDLINE | ID: mdl-19106219

ABSTRACT

Previous studies have shown reduced hypothalamo-pituitary-adrenal responses to both acute and chronic restraint stressors in rats allowed to ingest highly palatable foods (32% sucrose +/- lard) prior to restraint. In this study we tested the effects of prior access (7 d) to chow-only, sucrose/chow, lard/chow, or sucrose/lard/chow diets on central corticotropin-releasing factor (CRF) expression in rats studied in two experiments, 15 and 240 min after onset of restraint. Fat depot, particularly intraabdominal fat, weights were increased by prior access to palatable food, and circulating leptin concentrations were elevated in all groups. Metabolite concentrations were appropriate for values obtained after stressors. For unknown reasons, the 15-min experiment did not replicate previous results. In the 240-min experiment, ACTH and corticosterone responses were inhibited, as previously, and CRF mRNA in the hypothalamus and oval nucleus of the bed nuclei of the stria terminalis were reduced by palatable foods, suggesting strongly that both neuroendocrine and autonomic outflows are decreased by increased caloric deposition and palatable food. In the central nucleus of the amygdala, CRF was increased in the sucrose-drinking group and decreased in the sucrose/lard group, suggesting that the consequence of ingestion of sucrose uses different neural networks from the ingestion of lard. The results suggest strongly that ingestion of highly palatable foods reduces activity in the central stress response network, perhaps reducing the feeling of stressors.


Subject(s)
Adrenocorticotropic Hormone/blood , Corticosterone/blood , Corticotropin-Releasing Hormone/blood , Energy Metabolism/physiology , Food , Stress, Physiological/physiology , Taste/physiology , Adipose Tissue/growth & development , Animals , Body Weight/physiology , Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , Energy Intake/physiology , Hypothalamus/metabolism , Insulin/blood , Leptin/blood , Male , Palate/physiology , Rats , Rats, Sprague-Dawley , Restraint, Physical/physiology , Restraint, Physical/psychology
6.
Am J Physiol Endocrinol Metab ; 294(1): E190-200, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17971508

ABSTRACT

The common hepatic branch of the vagus nerve negatively regulates lard intake in rats with streptozotocin (STZ)-induced, insulin-dependent diabetes. However, this branch consists of two subbranches: the hepatic branch proper, which serves the liver, and the gastroduodenal branch, which serves the distal stomach, pancreas, and duodenum. The aim of this study was to determine whether the gastroduodenal branch specifically regulates voluntary lard intake. We performed a gastroduodenal branch vagotomy (GV) on nondiabetic, STZ-diabetic, and STZ-diabetic insulin-treated groups of rats and compared them with sham-operated counterparts. All rats had high steady-state corticosterone levels to maximize lard intake. Five days after surgery, all rats were provided with the choice of chow or lard to eat for another 5 days. STZ-diabetes resulted in a reduction in lard intake that was partially rescued by either GV or insulin treatment. Patterns of white adipose tissue (WAT) deposition differed after GV- and insulin-induced lard intake, with subcutaneous WAT increasing exclusively after the former and mesenteric WAT increasing exclusively in the latter. GV also prevented the insulin-induced reduction in the STZ-elevated plasma glucagon, triglycerides, free fatty acids, and total ketone bodies but did not alter the effect of insulin-induced reduction of plasma glucose levels. These data suggest that the gastroduodenal branch of the vagus inhibits lard intake and regulates WAT deposition and plasma metabolite levels in STZ-diabetic rats.


Subject(s)
Body Fat Distribution , Diabetes Mellitus, Experimental/metabolism , Liver/innervation , Liver/metabolism , Vagus Nerve/physiology , Animals , Blood Glucose/metabolism , Corticosterone/blood , Diabetes Mellitus, Experimental/drug therapy , Dietary Fats/pharmacology , Eating/physiology , Fatty Acids/blood , Gastric Inhibitory Polypeptide/blood , Glucagon/blood , Glycogen/metabolism , Hypoglycemic Agents/blood , Hypoglycemic Agents/pharmacology , Insulin/blood , Insulin/pharmacology , Male , Rats , Rats, Sprague-Dawley , Vagotomy , Vagus Nerve/anatomy & histology , Weight Loss/physiology
7.
ScientificWorldJournal ; 7: 203-12, 2007 Nov 02.
Article in English | MEDLINE | ID: mdl-17982594

ABSTRACT

Circadian rhythms prepare organisms for predictable events in the 24 h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.


Subject(s)
Circadian Rhythm/drug effects , Substance-Related Disorders/physiopathology , Animals , Behavior, Animal/physiology , Circadian Rhythm/physiology , Circadian Rhythm/radiation effects , Humans , Physical Conditioning, Animal/physiology
8.
Peptides ; 28(7): 1453-60, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17586086

ABSTRACT

It is becoming increasingly evident that the urocortins (Ucns) and their receptors are involved in the initiation and development of inflammation in the gastrointestinal (GI) tract. There has not been a systematic study of the basal expression of Ucns or their receptors in the GI tract. Here, we examined basal expression of Ucn 2 and its high-affinity receptor, CRF-R2 in the rat GI tract. Ucn 2 mRNA was expressed throughout the small and large intestine. Surprisingly, CRF-R2 mRNA expression was detected in only a subset of GI regions that expressed Ucn 2. Immunohistochemical study showed that both Ucn 2 immuno-reactivity (Ucn 2-IR) and CRF-R2-IR were consistently seen in the neurons of the myenteric plexus and the nerve fibers innervating the circular muscle. By and large, Ucn 2-IR was detected in all layers, including the mucosal and the submucosal layers throughout the GI regions. In contrast, CRF-R2-IR was very low or undetectable in the mucosal layers of all regions examined. The role of Ucn 2 and CRF-R2 was then examined in a rat model of chemically-induced colitis. In the early phase of colitis, Ucn 2 mRNA levels peaked, whereas, in striking contrast, CRF-R2 mRNA expression decreased approximately 2.5-fold below control levels. At the peptide level, Ucn 2-IR was specifically induced in a large population of immune cells that infiltrated the lamina propria and submucosa of the distal colon, whereas CRFR2-IR was detected in only a small fraction of infiltrated immune cells. CRF-R2-IR was dramatically reduced in the neurons of the myenteric plexus. Thus, we show, for the first time, that in the acute phase of inflammation, Ucn 2 levels are increased whereas expression levels of its only identified receptor, CRF-R2, are decreased. This suggests that Ucn 2 exerts its effects only in part via CRF-R2.


Subject(s)
Colitis/metabolism , Corticotropin-Releasing Hormone/metabolism , Gastrointestinal Tract/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Urocortins/metabolism , Animals , Colitis/chemically induced , Colitis/immunology , Colon/metabolism , Colon/pathology , Corticotropin-Releasing Hormone/genetics , Disease Models, Animal , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/genetics , Time Factors , Trinitrobenzenesulfonic Acid/pharmacology , Urocortins/genetics
9.
J Physiol ; 583(Pt 2): 455-67, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17584842

ABSTRACT

The common hepatic branch of the vagus nerve is a two-way highway of communication between the brain and the liver, duodenum, stomach and pancreas that regulates many aspects of food intake and metabolism. In this study, we utilized the afferent-specific neurotoxin capsaicin to examine if common hepatic vagal sensory afferents regulate lard intake. Rats implanted with a corticosterone pellet were made diabetic using streptozotocin (STZ) and a subset received steady-state exogenous insulin replacement into the superior mesenteric vein. These were compared with non-diabetic counterparts. Each group was then subdivided into those whose common hepatic branch of the vagus was treated with vehicle or capsaicin. Five days after surgery, the rats were offered the choice of chow and lard to consume for a further 5 days. The STZ-diabetic rats ate significantly less lard than the non-diabetic rats. Capsaicin treatment restored lard intake to that of the insulin-replaced, STZ-diabetic rats, but modified neither chow nor total caloric intake. This increased lard intake led to selective fat deposition into the mesenteric white adipose tissue depot, as opposed to an increase in all visceral fat pad depots evident after insulin replacement-induced lard intake. Capsaicin treatment also increased the levels of circulating glucose and triglycerides and negated the actions of insulin on these and free fatty acids and ketone bodies. Collectively, these data suggest that afferent signalling through the common hepatic branch of the vagus inhibits lard, but not chow, intake, directs fat deposition and regulates plasma metabolite levels.


Subject(s)
Biomarkers/blood , Diabetes Mellitus, Experimental/physiopathology , Dietary Fats/metabolism , Feeding Behavior , Liver/innervation , Vagus Nerve/physiopathology , Adipose Tissue, White/pathology , Adrenal Glands/pathology , Afferent Pathways/physiopathology , Animals , Blood Glucose/metabolism , Body Weight , Capsaicin/pharmacology , Corticosterone/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Dietary Fats/administration & dosage , Feeding Behavior/drug effects , Food Preferences , Glucagon/blood , Glycogen/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin/blood , Insulin/pharmacology , Insulin/therapeutic use , Leptin/blood , Lipids/blood , Liver/metabolism , Male , Organ Size , Rats , Rats, Sprague-Dawley , Spleen/pathology , Thymus Gland/pathology , Time Factors , Vagus Nerve/drug effects
10.
J Physiol ; 583(Pt 2): 431-6, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17556388

ABSTRACT

Glucocorticoids act primarily in a feed-forward fashion on brain to activate CNS pathways that implement wanting appropriate to physiological needs. Thus, depending on the available conditions, elevated glucocorticoids may augment the behavioural want to run, fight or feed. Although glucocorticoids stimulate intake of chow, fat and sucrose, insulin appears to sculpt calorie-associated desires toward foods high in fat, acting through hepatic branch afferents of the vagus nerve. Both conditions of reduced food allowance and chronic stress excite glucocorticoid-augmented central neural networks that may lead toward ultimate abdominal obesity.


Subject(s)
Brain/metabolism , Energy Intake , Feeding Behavior , Glucocorticoids/metabolism , Insulin/metabolism , Obesity/metabolism , Adrenalectomy , Animals , Brain/physiopathology , Dietary Fats/metabolism , Dietary Sucrose/metabolism , Feedback, Physiological , Humans , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Liver/innervation , Liver/metabolism , Obesity/physiopathology , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/physiopathology , Vagus Nerve/physiopathology
11.
Endocrinology ; 148(7): 3288-98, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17412812

ABSTRACT

Although high insulin concentrations reduce food intake, low insulin concentrations promote lard intake over chow, possibly via an insulin-derived, liver-mediated signal. To investigate the role of the hepatic vagus in voluntary lard intake, streptozotocin-diabetic rats with insulin or vehicle replaced into either the superior mesenteric or jugular veins received a hepatic branch vagotomy (HV) or a sham operation. All rats received a pellet of corticosterone that clamped the circulating steroid at moderately high concentrations to enhance lard intake. After 5 d of recovery, rats were offered the choice of lard and chow for 5 d. In streptozotocin-diabetic rats, HV, like insulin replacement, restored lard intake to nondiabetic levels. Consequently, this reduced chow intake without affecting total caloric intake, and insulin site-specifically increased white adipose tissue weight. HV also ablated the effects of insulin on reducing circulating glucose levels and attenuated the streptozotocin-induced weight loss in most groups. Collectively, these data suggest that the hepatic vagus normally inhibits lard intake and can influence glucose homeostasis and the pattern of white adipose tissue deposition. These actions may be modulated by insulin acting both centrally and peripherally.


Subject(s)
Adipose Tissue, White/metabolism , Diabetes Mellitus, Experimental/therapy , Dietary Fats/metabolism , Insulin/pharmacology , Vagotomy/methods , Adipose Tissue, White/drug effects , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Corticosterone/administration & dosage , Corticosterone/pharmacology , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/physiopathology , Dietary Fats/administration & dosage , Energy Intake/drug effects , Fatty Acids, Nonesterified/blood , Glycogen/metabolism , Hypoglycemic Agents/pharmacology , Insulin/blood , Ketone Bodies/blood , Male , Rats , Rats, Sprague-Dawley , Streptozocin , Time Factors , Triglycerides/blood , Vagus Nerve/physiopathology
12.
Curr Alzheimer Res ; 4(2): 199-204, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17430247

ABSTRACT

In mammals, glucocorticoid actions appear to have evolved to maintain and enhance energy stores to be used for life-saving gluconeogenesis. They act on the brain to stimulate search behaviors, palatable feeding and emotionally relevant memories, and they act on the body to mobilize stored peripheral energy and direct it to central depots that serve the substrate needs of the liver. Our work in rats shows that searching and intake of palatable foods (sucrose, saccharin and lard) are stimulated by corticosterone in a dose-related fashion. Adrenalectomized rats gain weight poorly, have low fat content, increased sympathetic neural and hypothalamo-pituitary-adrenal outflow, and altered behaviors. Replacement with corticosterone reverses these effects. Surprisingly, when such rats are provided with 30% sucrose to drink, in addition to saline, all of the usual effects of adrenalectomy are corrected without corticosterone. We hypothesize that there is a metabolic feedback system that decreases stress-responsiveness. Although we have not yet identified the signal associated with sucrose drinking, the weight of mesenteric fat correlates inversely with hypothalamic corticotropin-releasing factor (CRF). When rats eat lard and sucrose ad libitum, fat stores increase and CRF, ACTH and corticosterone responses are reduced. During stress, chow intake decreases but intake of lard and sucrose does not. Our current working model suggests that palatability signals and neural signals from fat stores act on brain to reduce activity in the central stress response system. Correlative results from a clinical study support the powerful role of small changes in glucocorticoids in type 2 diabetes.


Subject(s)
Glucocorticoids/metabolism , Metabolic Diseases/etiology , Obesity/etiology , Animals , Humans , Insulin/metabolism , Metabolic Diseases/metabolism , Metabolic Diseases/pathology , Models, Biological , Obesity/metabolism , Obesity/pathology , Risk Factors
13.
Prog Brain Res ; 153: 75-105, 2006.
Article in English | MEDLINE | ID: mdl-16876569

ABSTRACT

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.


Subject(s)
Glucocorticoids/metabolism , Obesity/metabolism , Stress, Physiological/metabolism , Animals , Chronic Disease , Humans , Hypothalamo-Hypophyseal System/metabolism , Pituitary-Adrenal System/metabolism
14.
Endocrinology ; 147(11): 5443-51, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16873535

ABSTRACT

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.


Subject(s)
Adipose Tissue/metabolism , Body Weight/drug effects , Diabetes Mellitus, Experimental/metabolism , Energy Intake/drug effects , Insulin/administration & dosage , Liver/physiology , Animals , Infusions, Intravenous , Jugular Veins , Male , Mesenteric Veins , Rats , Rats, Sprague-Dawley , Streptozocin
15.
Brain Behav Immun ; 19(4): 275-80, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15944067

ABSTRACT

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.


Subject(s)
Corticotropin-Releasing Hormone/metabolism , Eating/psychology , Food Preferences/psychology , Obesity/complications , Stress, Physiological/psychology , Animals , Chronic Disease , Eating/physiology , Glucocorticoids/physiology , Humans , Limbic System/physiology , Macaca mulatta , Neural Pathways/metabolism , Obesity/psychology , Rats , Self Medication/psychology , Stress, Physiological/complications , Stress, Physiological/physiopathology
16.
Endocrinology ; 145(6): 2633-8, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15044359

ABSTRACT

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.


Subject(s)
Abdomen , Eating/physiology , Glucocorticoids/physiology , Obesity/etiology , Socioeconomic Factors , Animals , Energy Metabolism/physiology , Humans , Insulin/physiology
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