The role of Neurochemicals, Stress Hormones and Immune System in the Positive Feedback Loops between Diabetes, Obesity and Depression

Type 2 diabetes mellitus (T2DM) and depression are significant public health and socioeconomic issues. They commonly co-occur, with T2DM occurring in 11.3% of the US population, while depression has a prevalence of about 9%, with higher rates among youths. Approximately 31% of patients with T2DM suffer from depressive symptoms, with 11.4% having major depressive disorders, which is twice as high as the prevalence of depression in patients without T2DM. Additionally, over 80% of people with T2DM are overweight or obese. This review describes how T2DM and depression can enhance one another, using the same molecular pathways, by synergistically altering the brain’s structure and function and reducing the reward obtained from eating. In this article, we reviewed the evidence that eating, especially high-caloric foods, stimulates the limbic system, initiating Reward Deficiency Syndrome. Analogous to other addictive behaviors, neurochemical changes in those with depression and/or T2DM are thought to cause individuals to increase their food intake to obtain the same reward leading to binge eating, weight gain and obesity. Treating the symptoms of T2DM, such as lowering HbA1c, without addressing the underlying pathways has little chance of eliminating the disease. Targeting the immune system, stress circuit, melatonin, and other alterations may be more effective

Alterations in Phosphorylated CREB Expression in Different Brain Regions following Short- and Long-Term Morphine Exposure: Relationship to Food Intake

Background. Activation of the cyclic adenosine monophosphate (cAMP)/phosphorylated CREB (P-CREB) system in different brain regions has been implicated in mediating opioid tolerance and dependence, while alteration of this system in the lateral hypothalamus (LH) has been suggested to have a role in food intake and body weight. Methods. Given that opioids regulate food intake, we measured P-CREB in different brain regions in mice exposed to morphine treatments designed to induce different degrees of tolerance and dependence. Results. We found that a single morphine injection or daily morphine injections for 8 days did not influence P-CREB levels, while the escalating dose of morphine regimen raised P-CREB levels only in the ventral tegmental area (VTA). Chronic morphine pellet implantation for 7 days raised P-CREB levels in the LH, VTA, and dorsomedial nucleus of the hypothalamus (DM) but not in the nucleus accumbens and amygdala. Increased P-CREB levels in LH, VTA, and DM following 7-day treatment with morphine pellets and increased P-CREB levels in the VTA following escalating doses of morphine were associated with decreased food intake and body weight. Conclusion. The morphine regulation of P-CREB may explain some of the physiological sequelae of opioid exposure including altered food intake and body weight

Increased Glycogen Synthase Kinase-3β and Hexose-6-Phosphate Dehydrogenase Expression in Adipose Tissue May Contribute to Glucocorticoid-Induced Mouse Visceral Adiposity

BACKGROUND Increased adiposity in visceral depots is a crucial feature associated with glucocorticoid (GC) excess. The action of GCs in target tissue is regulated by GC receptor (GR) and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6pdh). Glycogen synthase kinase-3β (GSK3β) is known to be a crucial mediator of ligand-dependent gene transcription. We hypothesized that the major effects of corticosteroids on adipose fat accumulation are in part medicated by changes in GSK3β and H6pdh. METHODS We characterized the alterations of GSK3β and GC metabolic enzymes, and determined the impact of GR antagonist mifepristone on obesity-related genes and the expression of H6pdh and 11ß-HSD1 in adipose tissue of mice exposed to excess GC as well as in in vitro studies using 3T3-L1 adipocytes treated with GCs. RESULTS Corticosterone (CORT) exposure increased abdominal fat mass and induced expression of lipid synthase ACC and ACL with activation of GSK3β phosphorylation in abdominal adipose tissue of C57BL/6J mice. Increased pSer9 GSK3β was correlated with induction of H6pdh and 11ß-HSD1. Additionally, mifepristone treatment reversed the production of H6pdh and attenuated CORT-mediated production of 11ß-HSD1 and lipogenic gene expression with reduction of pSer9 GSK3β, thereby leading to improvement of phenotype of adiposity within adipose tissue in mice treated with excess GCs. Suppression of pSer9 GSK3β by mifepristone was accompanied by activation of pThr308 Akt and blockade of CORT-induced adipogenic transcriptor C/EBPα and PPARγ. In addition, mifepristone also attenuated CORT-mediated activation of IRE1α/XBP1. Additionally, reduction of H6pdh by shRNA showed comparable effects to mifepristone on attenuating CORT-induced expression of GC metabolic enzymes and improved lipid accumulation in vitro in 3T3-L1 adipocytes. CONCLUSION These findings suggest that elevated adipose GSK3β and H6pdh expression contribute to 11ß-HSD1 mediating hypercortisolism associated with visceral adiposity

Opioid Crisis-An Emphasis on Fentanyl Analogs.

Opioids are the mainstay for the management of moderate to severe pain. However, their acute use is associated with several side effects, ranging from nausea, itching, sedation, hypotension to respiratory depression, and death. Also, chronic use of these drugs can lead to the development of tolerance, dependence, and eventually addiction. The most serious side effect, lethality due to opioid-induced overdose, has reached the level of national emergency, i.e., the opioid crisis, which is now the forefront of medicine. In a detailed review (Novel Synthetic Opioids: The Pathologist's Point of View), Frisoni and colleagues have discussed the side effects of novel licit and illicit fentanyl derivatives, as well as the related compounds which are more potent and faster acting than morphine and other conventional opioids (Frisoni, et al., 2018). These drugs affect the central nervous system (CNS) and can promote the development of addiction due to the quick rush they induce because of their faster entry into the brain. These drugs also arrest the cardiovascular and pulmonary systems, increasing the chance of respiratory arrest, leading to opioid-induced overdose morbidity and mortality. The respiratory arrest induced by opioids can be potentiated by other CNS depressants, such as alcohol or benzodiazepines, and therefore may occur more frequently in polydrug users. Therefore, the use of these newer fentanyl derivatives as well as other fast acting opioids should be avoided or limited to specific cases and must be kept out of the reach of children and adolescents who are more vulnerable to become addicted or overdose themselves

Opioid Crisis-An Emphasis on Fentanyl Analogs.

Opioids are the mainstay for the management of moderate to severe pain. However, their acute use is associated with several side effects, ranging from nausea, itching, sedation, hypotension to respiratory depression, and death. Also, chronic use of these drugs can lead to the development of tolerance, dependence, and eventually addiction. The most serious side effect, lethality due to opioid-induced overdose, has reached the level of national emergency, i.e., the opioid crisis, which is now the forefront of medicine. In a detailed review (Novel Synthetic Opioids: The Pathologist's Point of View), Frisoni and colleagues have discussed the side effects of novel licit and illicit fentanyl derivatives, as well as the related compounds which are more potent and faster acting than morphine and other conventional opioids (Frisoni, et al., 2018). These drugs affect the central nervous system (CNS) and can promote the development of addiction due to the quick rush they induce because of their faster entry into the brain. These drugs also arrest the cardiovascular and pulmonary systems, increasing the chance of respiratory arrest, leading to opioid-induced overdose morbidity and mortality. The respiratory arrest induced by opioids can be potentiated by other CNS depressants, such as alcohol or benzodiazepines, and therefore may occur more frequently in polydrug users. Therefore, the use of these newer fentanyl derivatives as well as other fast acting opioids should be avoided or limited to specific cases and must be kept out of the reach of children and adolescents who are more vulnerable to become addicted or overdose themselves

The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction.

Cocaine addiction is a global public health and socioeconomic issue that requires pharmacological and cognitive therapies. Currently there are no FDA-approved medications to treat cocaine addiction. However, in preclinical studies, interventions ranging from herbal medicine to deep-brain stimulation have shown promise for the therapy of cocaine addiction. Recent developments in molecular biology, pharmacology, and medicinal chemistry have enabled scientists to identify novel molecular targets along the pathways involved in drug addiction. In 1994, a receptor that showed a great deal of homology to the traditional opioid receptors was characterized. However, endogenous and exogenous opioids failed to bind to this receptor, which led scientists to name it opioid receptor-like receptor, now referred to as the nociceptin receptor. The endogenous ligand of NOPr was identified a year later and named orphanin FQ/nociceptin. Nociceptin and NOPr are widely distributed throughout the CNS and are involved in many physiological responses, such as food intake, nociceptive processing, neurotransmitter release, etc. Furthermore, exogenous nociceptin has been shown to regulate the activity of mesolimbic dopaminergic neurons, glutamate, and opioid systems, and the stress circuit. Importantly, exogenous nociceptin has been shown to reduce the rewarding and addictive actions of a number of drugs of abuse, such as psychostimulants, alcohol, and opioids. This paper reviews the existing literature on the role of endogenous nociceptin in the rewarding and addictive actions of cocaine. The effect of exogenous nociceptin on these processes is also reviewed. Furthermore, the effects of novel small-molecule NOPr ligands on these actions of cocaine are discussed. Overall, a review of the literature suggests that NOPr could be an emerging target for cocaine addiction pharmacotherapy