Ethanol-induced lymphatic endothelial cell permeability via MAP-kinase regulation.

Chronic alcohol alters the immune system enhancing the susceptibility to inflammation, bacterial, and viral infections in alcohol users. We have shown that alcohol causes increased permeability of mesenteric lymphatic vessels in alcohol-fed rats. The mechanisms of alcohol-induced lymphatic leakage are unknown. Endothelial cell monolayer permeability is controlled by junctional proteins complexes called tight junctions (TJ) and adherens junctions (AJ), and each can be regulated by MAPK activation. We hypothesize that ethanol induces lymphatic endothelial cell (LEC) permeability via disruption of LEC TJ through MAPK activation. An in vitro model of rat LECs was used. Ethanol-supplemented medium was added at concentrations of 0, 25, and 50 mM to confluent cells. Resistance-based barrier function, transwell permeability, cell viability, TJ, AJ, and MAPK protein activity, TJ and AJ gene expressions, and the role of p38 MAPK in barrier function regulation were measured. Ethanol increased the permeability of LECs compared to controls that was not associated with decreased cell viability. LECs treated with 50 mM ethanol showed an increase in phosphorylated levels of p38. No significant changes in TJ and AJ gene or protein expressions were observed after ethanol treatment. p38 inhibition prevented ethanol-induced increases in permeability. These findings suggest that p38 may play a role in the regulation of ethanol-induced LEC permeability, but altered permeability may not be associated with decreased TJ or AJ protein expression. Further investigation into junctional protein localization is needed to better understand the effects of ethanol on lymphatic endothelial cell-to-cell contacts and hyperpermeability.

The expression and function of growth hormone secretagogue receptor in immune cells: A current perspective.

The orexigenic hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), have been extensively studied in the last two decades, revealing that ghrelin signaling has important implications in health and disease. Metabolic diseases, such as obesity and diabetes, are often accompanied by low-grade chronic inflammation, that has been coined as "meta-inflammation." Immune cells are key cellular mediators of meta-inflammation, controlling both initiation and resolution of inflammation. Immune cells exhibit dynamic changes in cellular characteristics and functional output in response to the stimuli/insults from their surrounding microenvironment. Emerging evidence shows that ghrelin has an important effect on inflammation, in addition to its well-known effects on metabolism. However, the cellular/molecular mechanism of ghrelin signaling in immunity is largely unknown because the knowledge in regard to the expression and function of GHS-R in immune cells is currently sparse. In this review, we have accumulated the recent findings related to the expression and functions of GHS-R in various immune cells under different physiological and pathological states. This review aims to inspire further investigation of the immunological roles of ghrelin signaling and advance the therapeutic applications of ghrelin signaling in meta-inflammation.

Leptin treatment prevents impaired hypoglycemic counterregulation induced by exposure to severe caloric restriction or exposure to recurrent hypoglycemia.

Hypoglycemia-associated autonomic failure (HAAF) is a maladaptive failure in glucose counterregulation in persons with diabetes (PWD) that is caused by recurrent exposure to hypoglycemia. The adipokine leptin is known to regulate glucose homeostasis, and leptin levels fall following exposure to recurrent hypoglycemia. Yet, little is known regarding how reduced leptin levels influence glucose counterregulation, or if low leptin levels are involved in the development of HAAF. The purpose of this study was to determine the effect of hypoleptinemia on the neuroendocrine responses to hypoglycemia. We utilized two separate experimental paradigms known to induce a hypoleptinemic state: 60% caloric restriction (CR) in mice and three days of recurrent hypoglycemia (3dRH) in rats. A sub-set of animals were also treated with leptin (0.5-1.0 µg/g) during the CR or 3dRH periods. Neuroendocrine responses to hypoglycemia were assessed 60 min following an IP insulin injection on the terminal day of the paradigms. CR mice displayed defects in hypoglycemic counterregulation, indicated by significantly lower glucagon levels relative to controls, 13.5 pmol/L (SD 10.7) versus 64.7 pmol/L (SD 45) (p = 0.002). 3dRH rats displayed reduced epinephrine levels relative to controls, 1900 pg/mL (SD 1052) versus 3670 pg/mL (SD 780) (p = 0.030). Remarkably, leptin treatment during either paradigm completely reversed this effect by normalizing glucagon levels in CR mice, 78.0 pmol/L (SD 47.3) (p = 0.764), and epinephrine levels in 3dRH rats, 2910 pg/mL (SD 1680) (p = 0.522). These findings suggest that hypoleptinemia may be a key signaling event driving the development of HAAF and that leptin treatment may prevent the development of HAAF in PWD.

Consuming a ketogenic diet leads to altered hypoglycemic counter-regulation in mice.

Ketogenic diets (KDs) are becoming increasingly popular for the treatment of diabetes, yet they are associated with increased frequency of hypoglycemia. Here we report that mice fed a KD display blunted glucagon release to hypoglycemia and neuroglucopenia, suggesting that consuming a KD may increase the risk for iatrogenic hypoglycemia.