The astrocyte-neuron lactate shunt (ANLS) hypothesis is the most widely accepted model of brain glucose metabolism. However, over the past decades, research has shown that neuronal and astrocyte plasma membrane receptors, in particular, GLUT2, Kir6.2 subunit of the potassium ATP-channel, SGLT-3 acting as glucosensors, play a pivotal role in brain glucose metabolism. Although both ANLS hypothesis and glucosensor model substantially improved our understanding of brain glucose metabolism, the latter appears to be gaining more attention in the scientific community as the former could not account for new research data indicating that hypothalamic and brainstem neurons may not require astrocyte-derived lactate for energy. More recently, emerging evidences suggest a crucial role of sweet taste receptors in brain glucose metabolism. Furthermore, a couple of intracellular molecules acting as glucosensors have been identified in central astrocytes and neurons. This review integrates new data on the mechanisms of brain glucose sensing and metabolism. The role of the glucosensors including the sweet taste T1R2 + T1R3-mediated brain glucose-sensing and metabolism in brain glucose metabolic disorders is discussed. Possible role of glucose sensors (GLUT2, K-ATPKir6.2, SGLT3, T1R2 + T1R3) in brain diseases involving metabolic dysfunctions and the therapeutic significance in targeting central glucosensors for the treatment of these brain diseases are also discussed.

Emerging Concepts in Brain Glucose Metabolic Functions: From Glucose Sensing to How the Sweet Taste of Glucose Regulates Its Own Metabolism in Astrocytes and Neurons.

Obesity has recently become a major global health problem. Epidemiologic studies indicate that obesity is an important risk factor for type 2 diabetes (T2DM), atherosclerosis and low testosterone in men. Importantly, testosterone replacement treatment (TRT) can improve the condition of these diseases. According to human and animal studies testosterone can act as an anti-inflammatory and anti- atherogenic factor leading to inhibition of the risk factors and consequence of T2DM and atherosclerosis. Consequences of these diseases include dysregulation in atherogenic factors such as apolipoproteins or pro-inflammatory mediators such as cytokines and chemokines and their receptors. The effect of testosterone on these factors remains unclear. The objective of the present study was to demonstrate whether testosterone has antiinflammatory and anti-atherogenic action and by which mechanisms. This was achieved by using in vivo human and mice studies as well as in vitro models. The in vivo human study was conducted on short and long term studies, to determine the effect of TRT on anti and pro-inflammatory cytokines, HDL fractions and apolipoproteins in diabetic hypogonadal patients. Samples of liver tissue from testicular feminization mice (Tfm) were studied to investigate the effect of testosterone therapy on mRNA expression of adiponectin, PP ARb/o, PAI-1, apolipoproteins and pro-inflammatory chemokines with their receptors. Additionally, models of cell culture were studied including human macrophage THP-1 cells and mouse 3T3L1 cells to study the effect of testosterone with or without blocked androgen receptor (AR) on CX3CR1 and CCR2 and pro-inflammatory cytokines in macrophage cells and on adiponectin, PP ARB/o, PAI-1, leptin and chemokines in adipocyte cells, respectively.In the clinical studies, a reduction in adiponectin levels after 3 months was seen in the short-term study and an increase in HDL2 and HDL2/HDL3 ratio in the long-term study. No significant effect of testosterone was observed on body composition and atherogenic factors in either the short or long-term studies. In the animal study, testosterone increased hepatic expression of mRNA adiponectin, PP ARB/o and PAI-1 mRNA expression in Tfm. In the cell culture studies, testosterone treatment increased CCR2 mRNA expression and decreased secretion of IL-8 and TNF level in the supernatant of THP-1 macrophages. Testosterone decreased secretion of CCL2 and CX3CL1 from 3T3L1 adipocytes while increasing PAI-1 mRNA expression in these cells. The action of testosterone was based on the type of cells and time, route and dose size of treatment. In conclusion, although testosterone therapy showed a positive effect on some risk factors of obesity and its associated conditions, negative effects were also seen. However the exact mechanism of action of testosterone that influences risk factors of obesity and its associated conditions in men with low testosterone remain unclear, therefore further studies are needed to fully elucidate the above finding.

The effect of testosterone on factors associated with diabetes, atherosclerosis and obesity.

Alzheimer's disease (AD) prevalence varies by sex, suggesting that sex chromosomes, sex hormones and/or their signaling could potentially modulate AD risk and progression. Low testosterone levels are reported in men with AD. Further, variation in the androgen receptor (AR) gene has been associated with AD risk and cognitive impairment. We assessed measures of plasma testosterone levels as a biomarker of AD in male participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Baseline testosterone levels were significantly different between clinical diagnosis groups [cognitively normal controls, mild cognitive impairment (MCI), or AD], with the lowest testosterone levels in men with AD. Lower baseline testosterone levels were associated with higher baseline clinical severity. Change in testosterone levels between baseline and 1-year follow-up varied by diagnosis; MCI had the greatest decreases in testosterone levels between baseline and 1-year follow-up. Despite differences by clinical diagnosis, there was no association between plasma testosterone and CSF biomarkers of AD pathology. We also tested single nucleotide polymorphisms (SNPs) in AR for association with AD risk in a separate cohort from ADNI and found 26 SNPs associated with risk for AD. The top associated SNP is predicted to be an expression quantitative trait locus for AR in multiple tissues, including brain, with the AD-associated risk allele predicted to confer lower AR expression. Our findings suggest a link between the androgen pathway and AD through Aβ/tau independent pathways. These effects may be most pronounced during conversion from MCI to dementia.

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Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer's Disease.

The purpose of the present study is to investigate the correlations between food intake behavior and job stress level and neuropeptide hormone concentrations. Job strain and food intake behavior were first identified using a self-reported questionnaire, concentrations of neuropeptide hormones (adiponectin, brain derived neurotrophic factor [BDNF], leptin, and ghrelin) were determined, and the correlations were analyzed. In the results, job strain showed significant correlations with adiponectin (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.001~1.498; p < 0.05) and BDNF (OR, 0.793; 95% CI, 0.646~0.974; p < 0.05), and ghrelin exhibited a significant correlation with food intake score (OR, 0.911; 95% CI, 0.842~0.985, p < 0.05). These results suggest that job stress affects food intake regulation by altering the physiological concentrations of neuropeptide hormones as well as emotional status.

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Job Stress and Neuropeptide Response Contributing to Food Intake Regulation.

Sunflower oil is a common edible oil in the world, which is highly prone to oxidative degradation during the frying process. The present study aimed to investigate the effects of products obtained from the thermal oxidation process of sunflower oil on metabolic indices, and the secretion status of leptin and ghrelin in rats. In vivo studies were designed after determining the rate of formation of active aldehydes and peroxide value in sunflower oil following 300°C in a period of 30-240 min. To this end, 36 rats in 6 separate groups were fed with 2 ml of normal saline, fresh sunflower oil, and heated oils at 30, 60, 120, and 240 min for 45 days. Finally, lipid profile changes and leptin/ghrelin secretion were examined, along with histological changes in the liver tissue. The results indicated a significant increase in serum LDL, VLDL and triglycerides, and a decrease in HDL, in the groups treated with heated oils. These changes were associated with a higher accumulation of triglycerides, active aldehydes, and histological changes in the hepatic tissue. Although the serum ghrelin level in the groups receiving heated oil did not change significantly compared to the fresh oil, the serum leptin level increased significantly in the groups receiving heated oil. According to our findings, increasing the time of sunflower oil heating enhanced the formation of active aldehydes, so that daily consumption of such oxidized oils might be associated with the occurrence of dyslipidemia, fatty liver and the development of leptin resistance. PRACTICAL APPLICATIONS: Sunflower oil is highly prone to oxidative degradation during the frying process. Increasing time of sunflower oil heating enhanced the formation of active aldehydes. Daily consumption of oxidized oils might be associated with the occurrence of dyslipidemia, fatty liver and the development of leptin resistance.

Thermally oxidized sunflower oil diet alters leptin/ghrelin balance and lipid profile in rats: Possible role of reactive aldehydes in dyslipidemia.

Background The effect of diet composition on the fat regulating hormones and its possible interaction with insulin is necessary to fully understand the mechanisms by which the body controls feed intake. Objective The objective of this work was to evaluate the relationship between ghrelin, leptin, adiponectin and insulin with respect to diet composition. Fasting and refeeding represent a natural challenge for stimulating basic functions to energy metabolism. Methods The present study was conducted on 40 male albino rats that were divided into 4 groups ( n  = 10): (I): fed ad/libitum, (II): fasted group, refed group allowed for 20 min refeeding with food stuffs divided into two groups, (III): carbohydrate meal, (IV): fat meal. The present study suggests a physiological interaction of ghrelin and leptin in the periphery. Elevated fasting ghrelin appears to modulate other hormonal systems that participate in the regulation of food intake. Ghrelin inhibition after feeding is related to different nutrients satiating capacity. In addition to feeding, several hormonal states have also been involved in the suppression of postprandial ghrelin production. Meal and insulin were found to acutely affect leptin concentration. Inverse change in ghrelin and leptin between fasting and refeeding state may indicate a role of gastric leptin in regulating ghrelin secretion. Positive correlation between adiponectin and insulin with both macronutrients suggests a role of adiponectin in enhancing insulin action. The fact that gastric leptin is stimulated by diet and ghrelin responses could be due to direct effects of multiple hormonal signals which require postgastric feed back on the stomach among the latters (glucose and insulin).

Strength and independence of associations between ghrelin, leptin, adiponectin and insulin in stimulating basic functions to energy metabolism

Angiopoietin related growth factor (AGF) is a liver derived factor that potently antagonizes obesity and insulin resistance (IR).The objective of this work is to determine AGF serum levels and eval...

Relationship between testosterone, sex hormone binding globulin, angiopoietin related growth factor and insulin resistance in normal weight and obese men

Hoda A. Nour

Papers

Strength and independence of associations between ghrelin, leptin, adiponectin and insulin in stimulating basic functions to energy metabolism

Relationship between testosterone, sex hormone binding globulin, angiopoietin related growth factor and insulin resistance in normal weight and obese men

Liraglutide treatment and acylcarnitine profiles in Egyptian obese insulin-resistant females.