James P. Warne

Palatable Foods, Stress, and Energy Stores Sculpt Corticotropin-Releasing Factor, Adrenocorticotropin, and Corticosterone Concentrations after Restraint

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.

Shaping the stress response : Interplay of palatable food choices, glucocorticoids, insulin and abdominal obesity

Activity of the hypothalamo-pituitary-adrenal (HPA) axis is regulated by a negative feedback loop that dampens central drive of the axis via the actions of the secreted glucocorticoids. Conversely, under conditions of chronic stress, glucocorticoids delivered centrally increase hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing factor (CRF) expression and the response to restraint. However, HPA axis activity and PVN CRF mRNA expression under chronic stress conditions are often reduced, implying other indirect peripheral or extra-hypothalamic glucocorticoid actions. Glucocorticoids chronically increase palatable food intake, which increases abdominal fat depots and circulating insulin levels, both of which negatively correlate with PVN CRF mRNA expression and may in turn dampen the response to stress. Such an effect is dependent on food choices, rather than total calories ingested. Considering stress is omnipresent in the workplace, palatable food ingestion may represent a means to combat the feeling of stress which is ultimately maladaptive when unresolved.

Glucocorticoids and insulin both modulate caloric intake through actions on the brain

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.

Glucocorticoids, the etiology of obesity and the metabolic syndrome.

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.

Retraction Notice to: Impairment of Central Leptin-Mediated PI3K Signaling Manifested as Hepatic Steatosis Independent of Hyperphagia and Obesity

Hepatic steatosis is generally thought to develop via peripheral mechanisms associated with obesity. We show that chronic central infusion of leptin suppresses hepatic lipogenic gene expression and reduces triglyceride content via stimulation of hepatic sympathetic activity. This leptin function is independent of feeding and body weight but requires phosphatidylinositol 3-kinase (PI3K) signaling. Attenuation of leptin-induced PI3K signaling, brought about by transgenic expression of phosphatase and tensin homolog (PTEN) in leptin receptor neurons, leads to decreased hepatic sympathetic tone and increased triglyceride levels without affecting adiposity or hepatic insulin signaling. Central leptins effects on hepatic norepinephrine levels and triglyceride content are blunted in these mutant mice. Simultaneous downregulation of PI3K and signal transducer and activator of transcription-3 (Stat3) in leptin receptor neurons does not exacerbate obesity but causes more severe hepatic steatosis. Together, our results indicate that central cellular leptin resistance in PI3K signaling manifests as hepatic steatosis without causing obesity.

Disengaging insulin from corticosterone: roles of each on energy intake and disposition

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.

Loss of Atg12, but not Atg5, in pro-opiomelanocortin neurons exacerbates diet-induced obesity

The autophagy-related proteins ATG12 and ATG5 form a covalent complex essential for autophagy. Here, we demonstrate that ATG12 has distinct functions from ATG5 in pro-opiomelanocortin (POMC)-expressing neurons. Upon high-fat diet (HFD) consumption, mice lacking Atg12 in POMC-positive neurons exhibit accelerated weight gain, adiposity, and glucose intolerance, which is associated with increased food intake, reduced ambulation, and decreased LEP/leptin sensitivity. Importantly, although genetic deletion of either Atg12 or Atg5 renders POMC neurons autophagy-deficient, mice lacking Atg5 in POMC neurons do not exhibit these phenotypes. Hence, we propose nonautophagic functions for ATG12 in POMC neurons that counteract excessive weight gain in response to HFD consumption.

Afferent signalling through the common hepatic branch of the vagus inhibits voluntary lard intake and modifies plasma metabolite levels in rats

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.

Rapid alteration of stress-induced hypothalamic–pituitary–adrenal hormone secretion in the rat: A comparison of glucocorticoids and cannabinoids

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.

Metabolic transceivers: in tune with the central melanocortin system

The central melanocortin system plays an essential role in the regulation of energy metabolism. Key to this regulation are the responses of neurons expressing proopiomelanocortin (POMC) and agouti-related protein (AgRP) to blood-borne metabolic signals. Recent evidence has demonstrated that POMC and AgRP neurons are not simply mirror opposites of each other in function and responsiveness to metabolic signals, nor are they exclusively first-order neurons. These neurons act as central transceivers, integrating both hormonal and neural signals, and then transmitting this information to peripheral tissues via the autonomic nervous system to coordinate whole-body energy metabolism. This review focuses on most recent developments obtained from rodent studies on the function, metabolic regulation, and circuitry of the central melanocortin system.