Western diet-induced obesity interferes with the HPA axis-blunting effects of palatable food in male rats.

Limited intermittent consumption of palatable food reduces HPA axis responses to stress in chow-fed rats, and this effect is dependent on the rewarding properties of the palatable food. However, obesity may be a state of reduced consummatory food reward, suggesting that palatable foods may be less effective at blunting HPA axis reactivity in the context of diet-induced obesity (DIO). To test this hypothesis, adult male Long-Evans rats were given unlimited access to Western (high-fat, high-sugar) diet (WD) vs. normal chow (controls). After 8 weeks of diet exposure, rats were given limited sucrose intake (LSI) consisting of additional twice-daily access to a small amount (4 ml) of either 3% or 30% sucrose drink, or water (controls) for 2 weeks. Rats then received an acute restraint stress challenge, with collection of tail blood samples for measurement of plasma corticosterone. WD-fed rats had increased caloric intake, body weight and adiposity, as expected. Rats offered LSI (3% or 30%) readily drank the maximal amount allowed (8 ml/day) and reduced their dietary intake to compensate for the sucrose calories, such that LSI did not alter body weight regardless of diet type. In chow-fed lean rats, LSI with either 3% or 30% sucrose reduced the plasma corticosterone response to restraint stress, but this effect was absent in WD-fed DIO rats. Together, these data support the hypothesis that obesity attenuates stress blunting by palatable foods and suggest the possibility that consequently, individuals with obesity may need to consume larger amounts of palatable food to obtain adequate stress relief.

Sexual dimorphism in intestinal absorption and lymphatic transport of dietary lipids.

Although the basic process of intestinal lipid absorption and transport is understood, many critical aspects remain unclear. One question in particular is whether intestinal lipid absorption and transport differ between the sexes. Using a well-established lymph fistula model, we found that intact female mice exhibited lower lymphatic output of triacylglycerol (TAG) than male mice. Further analysis revealed that the female mice segregated into two groups: the high group having similar lymphatic TAG transport to the males, and the low group having significantly less lymphatic output, implying the impact of cyclical variation of ovarian hormonal levels. These led us to examine whether oestradiol (E2) and progesterone (P) affect intestinal absorption and lymphatic transport of dietary lipids. In ovariectomized (OVX) rats, E2 treatment significantly reduced [3 H]-TAG lymphatic output through reducing TAG transport; and P treatment decreased [14 C]cholesterol (Chol) lymphatic output by inhibiting Chol absorption, compared to vehicle treatment. Gene expression data suggested that E2 enhances vascular endothelial growth factor-A (VEGF-A) signalling to reduce the permeability of lacteals, leading to reduced CM transport through the lymphatic system. Interestingly, E2 treatment also increased lymphatic output of apolipoprotein A-I (apoA-I), but not apoB-48 and apoA-IV, in the OVX rats. Collectively, these data suggested that ovarian hormone-induced reductions of intestinal lipid absorption and lymphatic transport, as well as increased lymphatic output of apoA-I, may contribute to a beneficial protection from atherosclerosis in females. KEY POINTS: Significant differences in intestinal lipid absorption and lymphatic transport were found between female and male animals. Oestrogen treatment significantly reduced [3 H]triacylglycerol (TAG) lymphatic output through suppressing TAG transport in ovariectomized (OVX) rats, and this effect is associated with enhanced vegfa gene expression in the intestine. Progesterone treatment significantly decreased the output of [14 C]cholesterol in lymph by inhibiting cholesterol absorption in the OVX rats. Oestrogen treatment also increased lymphatic output of apolipoprotein A-I (apoA-I) in the OVX rats, which may contribute to the reduced risk of atherosclerosis in females.

Limited cheese intake reduces HPA axis and behavioral stress responses in male rats.

Eating palatable foods reduces behavioral and hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress - an idea referred to by the colloquial term "comfort" food. To study the underlying stress-relieving mechanisms of palatable foods, we previously developed a paradigm of limited sucrose feeding in which male rats are given twice-daily access to a small amount of sucrose drink and subsequently have reduced stress responses. Prior research in humans and rodents implicates high dietary sugars/carbohydrates with reduced stress responsivity. However, it is not clear whether the stress-relieving effects of the limited sucrose paradigm depend upon its macronutrient content. To test this idea, the current work measures stress responses in male rats following the limited intermittent intake of cheese - a highly palatable food that is low in sugar and other carbohydrates. The data show that a history of limited cheese intake (LCI) reduced HPA axis responses to acute psychological (restraint) and physiological (hypoxia) stressors. LCI also reduced behavioral struggling during restraint, increased sociability during a social interaction test, and increased open arm activity in the elevated plus-maze test. Z-score analyses evaluated the extent to which these behavioral effects extended within and across assays, and indicated that there was an overall reduction in stress-related behaviors following LCI. Finally, LCI increased immunolabeling for FosB/deltaFosB (a protein associated with repeated or chronic neuronal activation) in the nucleus accumbens. These results indicate that palatable foods can provide stress blunting regardless of their sugar/carbohydrate composition, and support the idea that food reward per se contributes to stress relief.

Differential Regulation of the Glucocorticoid Receptor in a Rat Model of Inflammatory Pain.

BACKGROUND: Anti-inflammatory corticosteroids are a common treatment for different conditions involving chronic pain and inflammation. Clinically used steroids target the glucocorticoid receptor (GR) for its anti-inflammatory effects. We previously reported that GR in sensory neurons may play central roles in some pain models and that GR immunoreactivity signal in dorsal root ganglia (DRG) decreased after local inflammation of the DRG (a model of low back pain). In the current study, we aimed to determine if similar changes in GR signal also exist in a skin inflammation model, the complete Freund's adjuvant (CFA) model (a model of peripheral inflammatory pain), in which the terminals of the sensory neurons rather than the somata are inflamed. METHODS: A low dose of CFA was injected into the hind paw to establish the peripheral inflammation model in Sprague-Dawley rats of both sexes, as confirmed by measurements of behavior and paw swelling. Immunohistochemical and western blotting techniques were used to determine the expression pattern of the GR in the inflamed hind paw and the DRGs. Plasma corticosterone levels were measured with radioimmunoassay. RESULTS: The immunohistochemical staining revealed that GR is widely expressed in the normal DRG and skin tissues. Paw injection with CFA caused upregulation of the GR in the skin tissue on postinjection day 1, mostly detected in the dermis area. However, paw inflammation significantly reduced the GR signal in the L5 DRG 1 day after the injection. The GR downregulation was still evident 14 days after CFA inflammation. On day 1, western blotting confirmed this downregulation and showed that it could also be observed in the contralateral L5 DRG, as well as in the L2 DRG (a level which does not innervate the paw). Plasma corticosterone levels were elevated in both sexes on day 14 after CFA compared to day 1, suggesting autologous downregulation of the GR by corticosterone may have contributed to the downregulation observed on day 14 but not day 1. CONCLUSIONS: There are distinctive patterns of GR activation under different pain conditions, depending on the anatomical location. The observed downregulation of the GR in sensory neurons may have a significant impact on the use of steroids as treatment in these conditions and on the regulatory effects of endogenous glucocorticoids.

Prefrontal Cortex Regulates Chronic Stress-Induced Cardiovascular Susceptibility.

Background The medial prefrontal cortex is necessary for appropriate appraisal of stressful information, as well as coordinating visceral and behavioral processes. However, prolonged stress impairs medial prefrontal cortex function and prefrontal-dependent behaviors. Additionally, chronic stress induces sympathetic predominance, contributing to health detriments associated with autonomic imbalance. Previous studies identified a subregion of rodent prefrontal cortex, infralimbic cortex (IL), as a key regulator of neuroendocrine-autonomic integration after chronic stress, suggesting that IL output may prevent chronic stress-induced autonomic imbalance. In the current study, we tested the hypothesis that the IL regulates hemodynamic, vascular, and cardiac responses to chronic stress. Methods and Results A viral-packaged small interfering RNA construct was used to knockdown vesicular glutamate transporter 1 (vGluT1) and reduce glutamate packaging and release from IL projection neurons. Male rats were injected with a vGluT1 small interfering RNA-expressing construct or GFP (green fluorescent protein) control into the IL and then remained as unstressed controls or were exposed to chronic variable stress. IL vGluT1 knockdown increased heart rate and mean arterial pressure reactivity, while chronic variable stress increased chronic mean arterial pressure only in small interfering RNA-treated rats. In another cohort, chronic variable stress and vGluT1 knockdown interacted to impair both endothelial-dependent and endothelial-independent vasoreactivity ex vivo. Furthermore, vGluT1 knockdown and chronic variable stress increased histological markers of fibrosis and hypertrophy. Conclusions Knockdown of glutamate release from IL projection neurons indicates that these cells are necessary to prevent the enhanced physiological responses to stress that promote susceptibility to cardiovascular pathophysiology. Ultimately, these findings provide evidence for a neurobiological mechanism mediating the relationship between stress and poor cardiovascular health outcomes.

Palatable food reduces anxiety-like behaviors and HPA axis responses to stress in female rats in an estrous-cycle specific manner.

Eating tasty foods dampens responses to stress - an idea reflected in the colloquial term 'comfort foods'. To study the neurobiological mechanisms by which palatable foods provide stress relief, we previously characterized a limited sucrose intake (LSI) paradigm in which male rats are given twice-daily access to 4 ml of 30% sucrose solution (vs. water as a control), and subsequently have reduced hypothalamic-pituitary-adrenocortical (HPA) axis responsivity and anxiety-related behaviors. Notably, women may be more prone to 'comfort feeding' than men, and this may vary across the menstrual cycle, suggesting the potential for important sex and estrous cycle differences. In support of this idea, LSI reduces HPA axis responses in female rats during the proestrus/estrus (P/E), as opposed to the diestrus 1/diestrus 2 (D1/D2) estrous cycle stage. However, the effect of LSI on anxiety-related behaviors in females remains unknown. Here we show that LSI reduced stress-related behaviors in female rats in the elevated plus-maze and restraint tests, but not in the open field test, though only during P/E. LSI also decreased the HPA axis stress response primarily during P/E, consistent with prior findings. Finally, cFos immunolabeling (a marker of neuronal activation) revealed that LSI increased post-restraint cFos in the central amygdala medial subdivision (CeM) and the bed nucleus of the stria terminalis posterior subnuclei (BSTp) exclusively during P/E. These results suggest that in female rats, palatable food reduces both behavioral and neuroendocrine stress responses in an estrous cycle-dependent manner, and the CeM and BSTp are implicated as potential mediators of these effects.

Effects of combined glucocorticoid/mineralocorticoid receptor modulation (CORT118335) on energy balance, adiposity, and lipid metabolism in male rats.

Psychological stress and excess glucocorticoids are associated with metabolic and cardiovascular diseases. Glucocorticoids act primarily through mineralocorticoid (MR) and glucocorticoid receptors (GR), and compounds modulating these receptors show promise in mitigating metabolic and cardiovascular-related phenotypes. CORT118335 (GR/MR modulator) prevents high-fat diet-induced weight gain and adiposity in mice, but the ability of this compound to reverse obesity-related symptoms is unknown. Adult male rats were subcutaneously administered CORT118335 (3, 10, or 30 mg/kg) or vehicle once daily. A 5-day treatment with CORT118335 at 30 mg/kg induced weight loss in rats fed a chow diet by decreasing food intake. However, lower doses of the compound attenuated body weight gain primarily because of decreased calorific efficiency, as there were no significant differences in food intake compared with vehicle. Notably, the body weight effects of CORT118335 persisted during a 2-wk treatment hiatus, suggesting prolonged effects of the compound. To our knowledge, we are the first to demonstrate a sustained effect of combined GR/MR modulation on body weight gain. These findings suggest that CORT118335 may have long-lasting effects, likely due to GR/MR-induced transcriptional changes. Prolonged (18 days) treatment of CORT118335 (10 mg/kg) reversed body weight gain and adiposity in animals fed a high-fat diet for 13 wk. Surprisingly, this occurred despite a worsening of the lipid profile and glucose homeostasis as well as a disrupted diurnal corticosterone rhythm, suggesting GR agonistic effects in the periphery. We conclude that species and tissue-specific targeting may result in promising leads for exploiting the metabolically beneficial aspects of GR/MR modulation.

Palatable Food Affects HPA Axis Responsivity and Forebrain Neurocircuitry in an Estrous Cycle-specific Manner in Female Rats.

Eating palatable foods can provide stress relief, but the mechanisms by which this occurs are unclear. We previously characterized a limited sucrose intake (LSI) paradigm in which twice-daily access to a small amount of 30% sucrose (vs. water as a control) reduces hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress and alters neuronal activation in stress-regulatory brain regions in male rats. However, women may be more prone to 'comfort feeding' behaviors than men, and stress-related eating may vary across the menstrual cycle. This suggests that LSI effects may be sex- and estrous cycle-dependent. The present study therefore investigated the effects of LSI on HPA axis stress responsivity, as well as markers of neuronal activation/plasticity in stress- and reward-related neurocircuitry in female rats across the estrous cycle. We found that LSI reduced post-restraint stress plasma ACTH in female rats specifically during proestrus/estrus (P/E). LSI also increased basal (non-stress) FosB/deltaFosB- and pCREB-immunolabeling in the basolateral amygdala (BLA) and central amygdala specifically during P/E. Finally, Bayesian network modeling of the FosB/deltaFosB and pCREB expression data identified a neurocircuit that includes the BLA, nucleus accumbens, prefrontal cortex, and bed nucleus of the stria terminalis as likely being modified by LSI during P/E. When considered in the context of our prior results, the present findings suggest that palatable food reduces stress responses in female rats similar to males, but in an estrous cycle-dependent manner. Further, the BLA may contribute to the LSI effects in both sexes, whereas the involvement of other brain regions appears to be sex-dependent.

High-fat diet exacerbates postoperative pain and inflammation in a sex-dependent manner.

Obesity is often associated with increased pain, but little is known about the effects of obesity and diet on postoperative pain. In this study, effects of diet and obesity were examined in the paw incision model, a preclinical model of postoperative pain. Long-Evans rats were fed high-fat diet (40% calories from butter fat) or low-fat normal chow. Male rats fed high-fat diet starting 6 weeks before incision (a diet previously shown to induce markers of obesity) had prolonged mechanical hypersensitivity and an overall increase in spontaneous pain in response to paw incision, compared with normal chow controls. Diet effects in females were minor. Removing high-fat diet for 2 weeks before incision reversed the diet effects on pain behaviors, although this was not enough time to reverse high-fat diet-induced weight gain. A shorter (1 week) exposure to high-fat diet before incision also increased pain behaviors in males, albeit to a lesser degree. The 6-week high-fat diet increased macrophage density as examined immunohistochemically in lumbar dorsal root ganglion even before paw incision, especially in males, and sensitized responses of peritoneal macrophages to lipopolysaccharide stimuli in vitro. The nerve regeneration marker growth-associated protein 43 (GAP43) in skin near the incision (day 4) was higher in the high-fat diet group, and wound healing was delayed. In summary, high-fat diet increased postoperative pain particularly in males, but some diet effects did not depend on weight gain. Even short-term dietary manipulations, that do not affect obesity, may enhance postoperative pain.

Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21.

In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thought to be modulated by an individual's nutritional environment. In this study, we report that nutritional manipulations signaling a relative depletion of dietary carbohydrates, thereby inducing nutritional ketosis, acutely and chronically activate the HPA axis. Male rats and mice maintained on a low-carbohydrate high-fat ketogenic diet (KD) exhibited canonical markers of chronic stress, including increased basal and stress-evoked plasma corticosterone, increased adrenal sensitivity to adrenocorticotropin hormone, increased stress-evoked c-Fos immunolabeling in the paraventricular nucleus of the hypothalamus, and thymic atrophy, an indicator of chronic glucocorticoid exposure. Moreover, acutely feeding medium-chain triglycerides (MCTs) to rapidly induce ketosis among chow-fed male rats and mice also acutely increased HPA axis activity. Lastly, and consistent with a growing literature that characterizes the hepatokine fibroblast growth factor-21 (FGF21) as both a marker of the ketotic state and as a key metabolic stress hormone, the HPA response to both KD and MCTs was significantly blunted among mice lacking FGF21. We conclude that dietary manipulations that induce ketosis lead to increased HPA axis tone, and that the hepatokine FGF21 may play an important role to facilitate this effect.

Adolescent environmental enrichment prevents behavioral and physiological sequelae of adolescent chronic stress in female (but not male) rats.

The late adolescent period is characterized by marked neurodevelopmental and endocrine fluctuations in the transition to early adulthood. Adolescents are highly responsive to the external environment, which enhances their ability to adapt and recover from challenges when given nurturing influences, but also makes them vulnerable to aberrant development when exposed to prolonged adverse situations. Female rats are particularly sensitive to the effects of chronic stress in adolescence, which manifests as passive coping strategies and blunted hypothalamo-pituitary adrenocortical (HPA) stress responses in adulthood. We sought to intervene by exposing adolescent rats to environmental enrichment (EE) immediately prior to and during chronic stress, hypothesizing that EE would minimize or prevent the long-term effects of stress that emerge in adult females. To test this, we exposed male and female rats to EE on postnatal days (PND) 33-60 and implemented chronic variable stress (CVS) on PND 40-60. CVS consisted of twice-daily unpredictable stressors. Experimental groups included: CVS/unenriched, unstressed/EE, CVS/EE and unstressed/unenriched (n = 10 of each sex/group). In adulthood, we measured behavior in the open field test and forced swim test (FST) and collected blood samples following the FST. We found that environmental enrichment given during the adolescent period prevented the chronic stress-induced transition to passive coping in the FST and reversed decreases in peak adrenocortical responsiveness observed in adult females. Adolescent enrichment had little to no effect on males or unstressed females tested in adulthood, indicating that beneficial effects are specific to females that were exposed to chronic stress.

High-fat diet increases pain behaviors in rats with or without obesity.

Obesity is associated with increased risk for chronic pain. Basic mechanisms for this association are poorly understood. Using a milder version of a radicular pain model, local inflammation of the dorsal root ganglion (DRG), we observed marked increases in mechanical and cold allodynia in rats of both sexes that were maintained on a high-fat diet (HFD) for 6 weeks prior to DRG inflammation. Notably, this increase in pain-related behaviors occurred in both Long-Evans and Sprague-Dawley rats despite the fact that the 6-week HFD exposure induced obesity (e.g., increased insulin, leptin, weight, and percent body fat) in the Long-Evans, but not Sprague-Dawley, strains. This suggested that HFD, rather than obesity per se, increased pain behaviors. Increased pain behaviors were observed even after a much shorter (1 week) exposure to the HFD but the effect was smaller. HFD also increased behavioral responses and paw swelling to paw injection of complete Freund's adjuvant, a model of peripheral inflammatory pain. No change was detected in plasma cytokine levels in HFD rats. However, increased macrophage infiltration of the DRG was observed in response to the HFD, absent any pain model. The results suggest that HFD can increase pain even when it does not cause obesity.

Apolipoprotein A-IV constrains HPA and behavioral stress responsivity in a strain-dependent manner.

There is a critical gap in our knowledge of the mechanisms that govern interactions between daily life experiences (e.g., stress) and metabolic diseases, despite evidence that stress can have profound effects on cardiometabolic health. Apolipoprotein A-IV (apoA-IV) is a protein found in chylomicrons (lipoprotein particles that transport lipids throughout the body) where it participates in lipid handling and the regulation of peripheral metabolism. Moreover, apoA-IV is expressed in brain regions that regulate energy balance including the arcuate nucleus. Given that both peripheral and central metabolic processes are important modulators of hypothalamic-pituitary-adrenocortical (HPA) axis activity, the present work tests the hypothesis that apoA-IV activity affects stress responses. As emerging data suggests that apoA-IV actions can vary with background strain, we also explore the strain-dependence of apoA-IV stress regulation. These studies assess HPA axis, metabolic (hyperglycemia), and anxiety-related behavioral responses to psychogenic stress in control (wildtype) and apoA-IV-deficient (KO) mice on either the C57Bl/6J (C57) or 129×1/SvJ (129) background strain. The results indicate that apoA-IV KO increases post-stress corticosterone and anxiety-related behavior specifically in the 129 strain, and increases stress-induced hyperglycemia exclusively in the C57 strain. These data support the hypothesis that apoA-IV is a novel factor that limits stress reactivity in a manner that depends on genetic background. An improved understanding of the complex relationship among lipid homeostasis, stress sensitivity, and genetics is needed to optimize the development of personalized treatments for stress- and metabolism-related diseases.

Vesicular Glutamate Transporter 1 Knockdown in Infralimbic Prefrontal Cortex Augments Neuroendocrine Responses to Chronic Stress in Male Rats.

Chronic stress-associated pathologies frequently associate with alterations in the structure and activity of the medial prefrontal cortex (mPFC). However, the influence of infralimbic cortex (IL) projection neurons on hypothalamic-pituitary-adrenal (HPA) axis activity is unknown, as is the involvement of these cells in chronic stress-induced endocrine alterations. In the current study, a lentiviral-packaged vector coding for a small interfering RNA (siRNA) targeting vesicular glutamate transporter (vGluT) 1 messenger RNA (mRNA) was microinjected into the IL of male rats. vGluT1 is responsible for presynaptic vesicular glutamate packaging in cortical neurons, and knockdown reduces the amount of glutamate available for synaptic release. After injection, rats were either exposed to chronic variable stress (CVS) or remained in the home cage as unstressed controls. Fifteen days after the initiation of CVS, all animals were exposed to a novel acute stressor (30-minute restraint) with blood collection for the analysis of adrenocorticotropic hormone (ACTH) and corticosterone. Additionally, brains were collected for in situ hybridization of corticotrophin-releasing hormone mRNA. In previously unstressed rats, vGluT1 siRNA significantly enhanced ACTH and corticosterone secretion. Compared with CVS animals receiving the green fluorescent protein control vector, the vGluT1 siRNA further increased basal and stress-induced corticosterone release. Further analysis revealed enhanced adrenal responsiveness in CVS rats treated with vGluT1 siRNA. Collectively, our results suggest that IL glutamate output inhibits HPA responses to acute stress and restrains corticosterone secretion during chronic stress, possibly at the level of the adrenal. Together, these findings pinpoint a neurochemical mechanism linking mPFC dysfunction with aberrant neuroendocrine responses to chronic stress.

Sucrose-induced plasticity in the basolateral amygdala in a 'comfort' feeding paradigm.

A history of intermittent, limited sucrose intake (LSI) attenuates the hypothalamic-pituitary-adrenocortical (HPA) axis stress response, and neuronal activity in the basolateral amygdala (BLA) is necessary for this HPA-dampening. LSI increases the expression of plasticity-associated genes in the BLA; however, the nature of this plasticity is unknown. As BLA principal neuron activity normally promotes HPA responses, the present study tests the hypothesis that LSI decreases stress-excitatory BLA output by decreasing glutamatergic and/or increasing GABAergic inputs to BLA principal neurons. Male rats with unlimited access to chow and water were given additional access to 4 ml of sucrose (30%) or water twice daily for 14 days, and BLA structural and functional plasticity was assessed by quantitative dual immunolabeling and whole-cell recordings in brain slices. LSI increased vesicular glutamate transporter 1-positive (glutamatergic) appositions onto parvalbumin-positive inhibitory interneurons, and this was accompanied by increased expression of pCREB, a marker of neuronal activation that is mechanistically linked with plasticity, within parvalbumin interneurons. LSI also increased the paired-pulse facilitation of excitatory, but not inhibitory synaptic inputs to BLA principal neurons, without affecting postsynaptic excitatory or miniature excitatory and inhibitory postsynaptic currents, suggesting a targeted decrease in the probability of evoked synaptic excitation onto these neurons. Collectively, these results suggest that LSI decreases BLA principal neuron output by increasing the excitatory drive to parvalbumin inhibitory interneurons, and decreasing the probability of evoked presynaptic glutamate release onto principal neurons. Our data further imply that palatable food consumption blunts HPA stress responses by decreasing the excitation-inhibition balance and attenuating BLA output.

Central Nervous System GLP-1 Receptors Regulate Islet Hormone Secretion and Glucose Homeostasis in Male Rats.

The glucagon-like peptide 1 (GLP-1) system plays an important role in blood glucose regulation, in great part through coordinate control of insulin and glucagon secretion. These effects are generally attributed to GLP-1 produced in peripheral sites, principally the intestine. GLP-1 is also produced in hindbrain neurons that signal through GLP-1 receptors (GLP-1rs) expressed in brain regions involved in metabolic regulation. GLP-1 in the central nervous system (CNS) induces satiety, visceral illness, and stress responses. However, recent evidence suggests CNS GLP-1 is also involved in glucose regulation. To test the hypothesis that central GLP-1 regulates islet hormone secretion, conscious rats were given intracerebroventricular (ICV) GLP-1, GLP-1r antagonist exendin-[9-39] (Ex-9), or saline during fasting or hyperglycemia from intravenous glucose. Administration of CNS GLP-1 increased fasting glucose, glucagon, corticosterone, and epinephrine and blunted insulin secretion in response to hyperglycemia. Paradoxically, GLP-1r blockade with ICV Ex-9 also reduced glucose-stimulated insulin secretion, and administration of ICV Ex-9 to freely feeding rats caused mild glucose intolerance. Thus, direct administration of CNS GLP-1 affected islet hormone secretion counter to what is seen with peripherally administered GLP-1, an effect likely due to stimulation of sympathetic nervous system activity. In contrast, blockade of brain GLP-1r supports a role for CNS GLP-1 on glucose-stimulated insulin secretion and glucose control after a meal. These findings suggest a model in which activation of CNS GLP-1r by endogenous peptide promotes glucose tolerance, an effect that can be overridden by stress responses stimulated by exogenous GLP-1.

Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress.

Organismal stress initiates a tightly orchestrated set of responses involving complex physiological and neurocognitive systems. Here, we present evidence for glucagon-like peptide 1 (GLP-1)-mediated paraventricular hypothalamic circuit coordinating the global stress response. The GLP-1 receptor (Glp1r) in mice was knocked down in neurons expressing single-minded 1, a transcription factor abundantly expressed in the paraventricular nucleus (PVN) of the hypothalamus. Mice with single-minded 1-mediated Glp1r knockdown had reduced hypothalamic-pituitary-adrenal axis responses to both acute and chronic stress and were protected against weight loss associated with chronic stress. In addition, regional Glp1r knockdown attenuated stress-induced cardiovascular responses accompanied by decreased sympathetic drive to the heart. Finally, Glp1r knockdown reduced anxiety-like behavior, implicating PVN GLP-1 signaling in behavioral stress reactivity. Collectively, these findings support a circuit whereby brainstem GLP-1 activates PVN signaling to mount an appropriate whole-organism response to stress. These results raise the possibility that dysfunction of this system may contribute to stress-related pathologies, and thereby provide a novel target for intervention. SIGNIFICANCE STATEMENT: Dysfunctional stress responses are linked to a number of somatic and psychiatric diseases, emphasizing the importance of precise neuronal control of effector pathways. Pharmacological evidence suggests a role for glucagon-like peptide-1 (GLP-1) in modulating stress responses. Using a targeted knockdown of the GLP-1 receptor in the single-minded 1 neurons, we show dependence of paraventricular nucleus GLP-1 signaling in the coordination of neuroendocrine, autonomic, and behavioral responses to acute and chronic stress. To our knowledge, this is the first direct demonstration of an obligate brainstem-to-hypothalamus circuit orchestrating general stress excitation across multiple effector systems. These findings provide novel information regarding signaling pathways coordinating central control of whole-body stress reactivity.

HPA Axis Interactions with Behavioral Systems.

Perhaps the most salient behaviors that individuals engage in involve the avoidance of aversive experiences and the pursuit of pleasurable experiences. Engagement in these behaviors is regulated to a significant extent by an individual's hormonal milieu. For example, glucocorticoid hormones are produced by the hypothalamic-pituitary-adrenocortical (HPA) axis, and influence most aspects of behavior. In turn, many behaviors can influence HPA axis activity. These bidirectional interactions not only coordinate an individual's physiological and behavioral states to each other, but can also tune them to environmental conditions thereby optimizing survival. The present review details the influence of the HPA axis on many types of behavior, including appetitively-motivated behaviors (e.g., food intake and drug use), aversively-motivated behaviors (e.g., anxiety-related and depressive-like) and cognitive behaviors (e.g., learning and memory). Conversely, the manuscript also describes how engaging in various behaviors influences HPA axis activity. Our current understanding of the neuronal and/or hormonal mechanisms that underlie these interactions is also summarized. © 2016 American Physiological Society. Compr Physiol 6:1897-1934, 2016.

Self-medication with sucrose.

For many individuals, stress promotes the consumption of sweet, high-sugar foods relative to healthier alternatives. Daily life stressors stimulate the overeating of highly-palatable foods through multiple mechanisms, including altered glucocorticoid, relaxin-3, ghrelin and serotonin signaling in brain. In turn, a history of consuming high-sugar foods attenuates the psychological (anxiety and depressed mood) and physiological (HPA axis) effects of stress. Together the metabolic and hedonic properties of sucrose contribute to its stress relief, possibly via actions in both the periphery (e.g., glucocorticoid receptor signaling in adipose tissue) and in the brain (e.g., plasticity in brain reward regions). Emerging work continues to reveal the bidirectional mechanisms that underlie the use of high-sugar foods as 'self-medication' for stress relief.