Gut-Brain Cross-Talk in Metabolic Control.

Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.

Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.

The Impact of Smoking in Workers' Compensation Patients Receiving Spinal Cord Stimulation.

The objective of this study was to determine the impact of smoking on clinical outcomes in workers' compensation (WC) patients receiving spinal cord stimulation (SCS). One hundred and ninety-six patients from the Ohio Bureau of Workers' Compensation were identified who received SCS with implantation occurring between 2007-2012. Patients were divided into smokers (n = 120) and nonsmokers (n = 76). Population characteristics before and after implantation were analyzed between the two groups. A multivariate logistic regression was run to determine predictors of return to work (RTW) status. Our regression determined smoking (p = 0.006; odds ratio [OR] = 0.260) and body mass index (p = 0.036; OR = 0.905) to be negative predictors of RTW status. After implantation, smokers were less likely to RTW after 6 months and had higher pain scores after 6 and 12 months. Both smokers and nonsmokers had significance reductions in opioid use after SCS implantation. (Journal of Surgical Orthopaedic Advances 30(3):185-189, 2021).

Grey literature citations in top nursing journals: a bibliometric study.

OBJECTIVE: As access to information grows in tandem with the growth of the Internet, access to grey literature also increases. Because little is known about the use of grey literature in nursing journals, the authors investigated the prevalence and types of grey literature citations in top nursing journals. METHODS: We analyzed all citations (n=52,116) from articles published in 2011 in 6 top nursing journals selected from the Medical Library Association's Nursing and Allied Health Resource Section's 2012 "Selected List of Nursing Journals." Grey literature citations were identified and categorized by type. RESULTS: Grey literature accounted for 10.4% of citations across all 6 journals. Publications from governments (54.3%) and corporate organizations (26.8%) were the most common types of grey literature. CONCLUSION: The substantial citation of grey literature in nursing journals shows that nursing scholars seek and use this category of information. These findings have implications for teaching and learning among nursing researchers and the information professionals who serve the nursing research community.

Receptor CD36 links a risk-associated allele to obesity and metabolic disorders.

Mice harboring a particular allele of the human brain-derived neurotropic factor (BDNFM/M mice) develop extreme obesity and insulin resistance when fed a high-fat diet. The underlying mechanisms of this genetic risk factor for obesity are unclear. In the current issue of JBC, Yang et al. report that pharmacological inhibition of integral membrane protein CD36 significantly reduces body weight gain and improves glucose tolerance in BDNFM/M mice. Targeting CD36 may therefore be a promising strategy to improve metabolic dysfunctions and normalize risk factors in obese individuals.

Silencing steroid receptor coactivator-1 in the nucleus of the solitary tract reduces estrogenic effects on feeding and apolipoprotein A-IV expression.

We previously found that 17ß-estradiol (E2) stimulates apolipoprotein A-IV (apoA-IV) gene expression in the nucleus of the solitary tract (NTS) of lean ovariectomized (OVX) rodents. Here we report that in the NTS of high-fat diet-induced obese (DIO) rats, the apoA-IV mRNA level is significantly reduced and that the estrogenic effects on apoA-IV gene expression and food intake are impaired. E2 regulates apoA-IV gene expression through its nuclear receptor α (ERα), which requires co-activators, such as steroid receptor coactivator-1 (SRC-1), to facilitate the transcription of targeted genes. Interestingly, SRC-1 gene expression is significantly reduced in DIO OVX rats. SRC-1 is colocalized with apoA-IV in the cells of the NTS and E2 treatment enhances the recruitment of ERα and SRC-1 to the estrogen response element at the apoA-V promoter, implying the participation of SRC-1 in E2's stimulatory effect on apoA-IV gene expression. Using small hairpin RNA (shRNA), which was validated in cultured neuronal cells, we found that SRC-1 gene knockdown specifically in the NTS significantly diminished E2's anorectic action, leading to increased food intake and body weight. More importantly, the stimulatory effect of E2 on apoA-IV gene expression in the NTS was significantly attenuated in SRC-1 knockdown rats. These results collectively demonstrate the critical roles of NTS SRC-1 in mediating E2's actions on food intake and apoA-IV gene expression and suggest that reduced levels of endogenous SRC-1 and apoA-IV expression are responsible for the impaired E2's anorectic action in obese females.

Cooperation between brain and islet in glucose homeostasis and diabetes.

Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as 'glucose effectiveness', account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.

Circulating HDL levels control hypothalamic astrogliosis via apoA-I.

Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I-/-) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I-/- compared with apoA-I+/+ mice and was associated with compromised mitochondrial function. apoA-I-/- mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I+/+ controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I-/- mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease.

Multilevel Lumbar Fusion Is a Risk Factor for Lower Return to Work Rates Among Workers' Compensation Subjects With Degenerative Disc Disease.

Discogenic fusion is associated with variable outcomes, especially if multiple levels are fused. This study sought to determine the impact of fused levels on return to work (RTW) status in a workers' compensation (WC) setting. Nine hundred thirty-seven subjects were selected for study. The primary outcome was the ability to RTW within 2 years following fusion and to sustain this level for greater than 6 months. Many secondary outcomes were collected. A multivariate logistic regression model was used to determine the impact of multilevel fusion on RTW status. Of the multilevel fusion group, 21.7% met the RTW criteria versus 28.1% of the single-level fusion group (p < .028). Multilevel fusion was a negative predictor of RTW status (p < .041; OR 0.71). Additional negative predictors included prolonged time out of work, male gender, chronic opioid analgesia, and legal representation. Multilevel fusion led to poor clinical outcomes while overall RTW rates were low, which suggests a limited role of discogenic fusion within the WC setting. (Journal of Surgical Orthopaedic Advances 27(3):209-218, 2018).

Lumbar Discography Is Associated With Poor Return to Work Status Following Lumbar Fusion Surgery in a Workers' Compensation Setting.

Lumbar discography (LD) is used to guide surgical decision making in patients with degenerative disc disease (DDD). Its safety and diagnostic accuracy are under contention. This study evaluates LD's efficacy within the workers' compensation (WC) population. Multivariate logistic regression analysis was used to determine the impact that undergoing LD before lumbar fusion for DDD had on return to work (RTW) rates among 1407 WC subjects. Discography was negatively associated with RTW status (p = .042; OR 0.76); 22.2% (142/641) of LD subjects met the RTW criteria, compared with 29.6% (227/766) of controls. Additional preoperative risk factors included psychological comorbidity (p < .001; OR 0.34), age greater than 50 (p < .005; OR 0.64), male gender (p < .037; OR 0.75), chronic opioid use (p < .001; OR 0.53), legal representation (p < .034; OR 0.72), and fusion technique (p < .043). LD subjects used postoperative narcotics for an average of 123 additional days (p < .001). This raises concerns regarding the utility of discography in the WC population. (Journal of Surgical Orthopaedic Advances 27(1):25-32, 2018).

Energy homeostasis in apolipoprotein AIV and cholecystokinin-deficient mice.

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

Examining conscientiousness as a key resource in resisting email interruptions: Implications for volatile resources and goal achievement.

Within the context of the conservation of resources model, when a resource is deployed, it is depleted - albeit temporarily. However, when a 'key', stable resource, such as Conscientiousness, is activated (e.g., using a self-control strategy, such as resisting an email interruption), we predicted that (1) another, more volatile resource (affective well-being) would be impacted and that (2) this strategy would be deployed as a trade-off, allowing one to satisfy task goals, at the expense of well-being goals. We conducted an experience-sampling field study with 52 email-users dealing with their normal email as it interrupted them over the course of a half-day period. This amounted to a total of 376 email reported across the sample. Results were analysed using random coefficient hierarchical linear modelling and included cross-level interactions for Conscientiousness with strategy and well-being. Our first prediction was supported - deploying the stable, key resource of Conscientiousness depletes the volatile, fluctuating resource of affective well-being. However, our second prediction was not fully realized. Although resisting or avoiding an email interruption was perceived to hinder well-being goal achievement by Conscientious people, it had neither a positive nor negative impact on task goal achievement. Implications for theory and practice are discussed. Practitioner points: It may be necessary for highly Conscientious people to turn off their email interruption alerts at work, in order to avoid the strain that results from an activation-resistance mechanism afforded by the arrival of a new email.Deploying key resources means that volatile resources may be differentially spent, depending on one's natural tendencies and how these interact with the work task and context. This suggests that the relationship between demands and resources is not always direct and predictable.Practitioners may wish to appraise the strategies they use to deal with demands such as email at work, to identify if these strategies are assisting with task or well-being goal achievement, or whether they have become defunct through automation.

PYY3-36: Beyond food intake.

The gastrointestinal hormone peptide tyrosine tyrosine 3-36 (PYY(3-36)) has attained broad recognition with respect to its involvement in energy homeostasis and the control of food intake. It is mainly secreted by distal intestinal enteroendocrine L-cells in response to eating and exerts neurally mediated, paracrine and endocrine effects on various target organs. In addition to its gastrointestinal effects, PYY(3-36) has long been known to inhibit food intake. Recent closer examination of the effects of PYY(3-36) revealed that this gut-derived peptide also influences a wide spectrum of behavioral and cognitive functions that are pivotal for basic processes of perception and judgment, including central information processing, salience learning, working memory, and behavioral responding to novelty. Here, we review the effects of PYY(3-36) that go beyond food intake and provide a conceptual framework suggesting that several apparently unrelated behavioral actions of PYY(3-36) may actually reflect different manifestations of modulating the central dopamine system.

The role of proximal versus distal stomach resection in the weight loss seen after vertical sleeve gastrectomy.

The mechanisms involved in the weight loss seen after vertical sleeve gastrectomy (VSG) are not clear. The rat stomach has two morphologically and functionally distinct proximal and distal parts. The rat model for VSG involves complete removal of the proximal part and 80% removal of the distal part along the greater curvature. The purpose of this study was to understand the potential independent contributions of removal of these distinct gastric sections to VSG outcomes. We prepared four surgical groups of male Long-Evans rats: VSG, sham surgery (control), selective proximal section removal (PR), and selective distal section removal (DR). Gastric emptying rate (GER) was highest after VSG compared with all other groups. However, PR, in turn, had significantly greater GER compared with both DR and sham groups. The surgery-induced weight loss followed the same pattern with VSG causing the greatest weight loss and PR having greater weight loss compared with DR and sham groups. The results were robust for rats fed regular chow or a high-fat diet. Body mass analysis revealed that the weight loss was due to the loss of fat mass, and there was no change in lean mass after the surgeries. In conclusion, removal of the proximal stomach contributes to most, but not all, of the physiological impact of VSG.

The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion.

Both glucagon-like peptide-1 (GLP-1) and apolipoprotein A-IV (apoA-IV) are produced from the gut and enhance postprandial insulin secretion. This study investigated whether apoA-IV regulates nutrient-induced GLP-1 secretion and whether apoA-IV knockout causes compensatory GLP-1 release. Using lymph-fistula-mice, we first determined lymphatic GLP-1 secretion by administering apoA-IV before an intraduodenal Ensure infusion. apoA-IV changed neither basal nor Ensure-induced GLP-1 secretion relative to saline administration. We then assessed GLP-1 in apoA-IV-/- and wild-type (WT) mice administered intraduodenal Ensure. apoA-IV-/- mice had comparable lymph flow, lymphatic triglyceride, glucose, and protein outputs as WT mice. Intriguingly, apoA-IV-/- mice had higher lymphatic GLP-1 concentration and output than WT mice 30 min after Ensure administration. Increased GLP-1 was also observed in plasma of apoA-IV-/- mice at 30 min. apoA-IV-/- mice had comparable total gut GLP-1 content relative to WT mice under fasting, but a lower GLP-1 content 30 min after Ensure administration, suggesting that more GLP-1 was secreted. Moreover, an injection of apoA-IV protein did not reverse the increased GLP-1 secretion in apoA-IV-/- mice. Finally, we assessed gene expression of GLUT-2 and the lipid receptors, including G protein-coupled receptor (GPR) 40, GPR119, and GPR120 in intestinal segments. GLUT-2, GPR40 and GPR120 mRNAs were unaltered by apoA-IV knockout. However, ileal GPR119 mRNA was significantly increased in apoA-IV-/- mice. GPR119 colocalizes with GLP-1 in ileum and stimulates GLP-1 secretion by sensing OEA, lysophosphatidylcholine, and 2-monoacylglycerols. We suggest that increased ileal GPR119 is a potential mechanism by which GLP-1 secretion is enhanced in apoA-IV-/- mice.

Apolipoprotein A-IV improves glucose homeostasis by enhancing insulin secretion.

Apolipoprotein A-IV (apoA-IV) is secreted by the small intestine in response to fat absorption. Here we demonstrate a potential role for apoA-IV in regulating glucose homeostasis. ApoA-IV-treated isolated pancreatic islets had enhanced insulin secretion under conditions of high glucose but not of low glucose, suggesting a direct effect of apoA-IV to enhance glucose-stimulated insulin release. This enhancement involves cAMP at a level distal to Ca(2+) influx into the ß cells. Knockout of apoA-IV results in compromised insulin secretion and impaired glucose tolerance compared with WT mice. Challenging apoA-IV(-/-) mice with a high-fat diet led to fasting hyperglycemia and more severe glucose intolerance associated with defective insulin secretion than occurred in WT mice. Administration of exogenous apoA-IV to apoA-IV(-/-) mice improved glucose tolerance by enhancing insulin secretion in mice fed either chow or a high-fat diet. Finally, we demonstrate that exogenous apoA-IV injection decreases blood glucose levels and stimulates a transient increase in insulin secretion in KKAy diabetic mice. These results suggest that apoA-IV may provide a therapeutic target for the regulation of glucose-stimulated insulin secretion and treatment of diabetes.

Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity.

Obesity is associated with increased levels of angiotensin-II (Ang-II), which activates angiotensin type 1a receptors (AT1a) to influence cardiovascular function and energy homeostasis. To test the hypothesis that specific AT1a within the brain control these processes, we used the Cre/lox system to delete AT1a from the paraventricular nucleus of the hypothalamus (PVN) of mice. PVN AT1a deletion did not affect body mass or adiposity when mice were maintained on standard chow. However, maintenance on a high-fat diet revealed a gene by environment interaction whereby mice lacking AT1a in the PVN had increased food intake and decreased energy expenditure that augmented body mass and adiposity relative to controls. Despite this increased adiposity, PVN AT1a deletion reduced systolic blood pressure, suggesting that this receptor population mediates the positive correlation between adiposity and blood pressure. Gene expression studies revealed that PVN AT1a deletion decreased hypothalamic expression of corticotrophin-releasing hormone and oxytocin, neuropeptides known to control food intake and sympathetic nervous system activity. Whole-cell patch-clamp recordings confirmed that PVN AT1a deletion eliminates responsiveness of PVN parvocellular neurons to Ang-II, and suggest that Ang-II responsiveness is increased in obese wild-type mice. Central inflammation is associated with metabolic and cardiovascular disorders and PVN AT1a deletion reduced indices of hypothalamic inflammation. Collectively, these studies demonstrate that PVN AT1a regulate energy balance during environmental challenges that promote metabolic and cardiovascular pathologies. The implication is that the elevated Ang-II that accompanies obesity serves as a negative feedback signal that activates PVN neurons to alleviate weight gain.

The role of the transcription factor ETV5 in insulin exocytosis.

AIMS/HYPOTHESIS: Genome-wide association studies have revealed an association of the transcription factor ETS variant gene 5 (ETV5) with human obesity. However, its role in glucose homeostasis and energy balance is unknown. METHODS: Etv5 knockout (KO) mice were monitored weekly for body weight (BW) and food intake. Body composition was measured at 8 and 16 weeks of age. Glucose metabolism was studied, and glucose-stimulated insulin secretion was measured in vivo and in vitro. RESULTS: Etv5 KO mice are smaller and leaner, and have a reduced BW and lower fat mass than their wild-type controls on a chow diet. When exposed to a high-fat diet, KO mice are resistant to diet-induced BW gain. Despite a greater insulin sensitivity, KO mice have profoundly impaired glucose tolerance associated with impaired insulin secretion. Morphometric analysis revealed smaller islets and a reduced beta cell size in the pancreatic islets of Etv5 KO mice. Knockdown of ETV5 in an insulin-secreting cell line or beta cells from human donors revealed intact mitochondrial and Ca(2+) channel activity, but reduced insulin exocytosis. CONCLUSION/INTERPRETATION: This work reveals a critical role for ETV5 in specifically regulating insulin secretion both in vitro and in vivo.

Meal feeding improves oral glucose tolerance in male rats and causes adaptations in postprandial islet hormone secretion that are independent of plasma incretins or glycemia.

Meal-fed (MF) rats with access to food for only 4 consecutive hours during the light cycle learn to eat large meals to maintain energy balance. MF animals develop behavioral and endocrine changes that permit glucose tolerance despite increased meal size. We hypothesized that enhanced activity of the enteroinsular axis mediates glucose homeostasis during MF. Cohorts of rats were allocated to MF or ad libitum (AL) regimens for 2-4 wk. Insulin secretion and glucose tolerance were determined after oral carbohydrate and intraperitoneal (ip) and intravenous (iv) glucose. MF rats ate less than AL in the first week but maintained a comparable weight trajectory thereafter. MF rats had decreased glucose excursions after a liquid mixed meal (AUC: MF 75 ± 7, AL 461 ± 28 mmol·l⁻¹·min, P < 0.001), with left-shifted insulin secretion (AUC(0-15): MF 31.0 ± 4.9, AL 9.6 ± 4.4 pM·min, P < 0.02), which peaked before a significant rise in blood glucose. Both groups had comparable fasting glucagon levels, but postprandial responses were lower with MF. However, neither intestinal expression of proGIP and proglucagon mRNA nor plasma incretin levels differed between MF and AL groups. There were no differences in the insulin response to ip or iv glucose between MF and AL rats. These findings demonstrate that MF improves oral glucose tolerance and is associated with significant changes in postprandial islet hormone secretion. Because MF enhanced ß-cell function during oral but not parenteral carbohydrate administration, and was not accounted for by changes in circulating incretins, these results support a neural mechanism of adaptive insulin secretion.