Slc12a2 loss in insulin-secreting ß-cells links development of overweight and metabolic dysregulation to impaired satiation control of feeding.

Male mice lacking the Na+-K+-2Cl- cotransporter Slc12a2 (Nkcc1) specifically in insulin-secreting ß-cells (Slc12a2ßKO) have reduced ß-cell mass and mild ß-cell secretory dysfunction associated with overweight, glucose intolerance, insulin resistance, and metabolic abnormalities. Here, we confirmed and extended previous results to female Slc12a2ßKO mice, which developed a similar metabolic syndrome-like phenotype as males, albeit milder. Notably, male and female Slc12a2ßKO mice developed overweight without consuming excess calories. Analysis of the feeding microstructure revealed that young lean Slc12a2ßKO male mice ate meals of higher caloric content and at a relatively lower frequency than normal mice, particularly during the night. In addition, overweight Slc12a2ßKO mice consumed significantly larger meals than lean mice. Therefore, the reduced satiation control of feeding precedes the onset of overweight and is worsened in older Slc12a2ßKO mice. However, the time spent between meals remained intact in lean and overweight Slc12a2ßKO mice, indicating conserved satiety responses to ad libitum feeding. Nevertheless, satiety was intensified during and after refeeding only in overweight males. In lean females, satiety responses to refeeding were delayed relative to age- and body weight-matched control mice but normalized in overweight mice. Since meal size did not change during refeeding, these data suggested that the satiety control of eating after fasting is impaired in lean Slc12a2ßKO mice before the onset of overweight and independently of their reduced satiation responses. Therefore, our results support the novel hypothesis that reduced satiation precedes the onset of overweight and the development of metabolic dysregulation.NEW & NOTEWORTHY Obesity, defined as excess fat accumulation, increases the absolute risk for metabolic diseases. Although obesity is usually attributed to increased food intake, we demonstrate that body weight gain can be hastened without consuming excess calories. In fact, impaired meal termination control, i.e., satiation, is detectable before the development of overweight in an animal model that develops a metabolic syndrome-like phenotype.

Loss of Slc12a2 specifically in pancreatic ß-cells drives metabolic syndrome in mice.

The risk of type-2 diabetes and cardiovascular disease is higher in subjects with metabolic syndrome, a cluster of clinical conditions characterized by obesity, impaired glucose metabolism, hyperinsulinemia, hyperlipidemia and hypertension. Diuretics are frequently used to treat hypertension in these patients, however, their use has long been associated with poor metabolic outcomes which cannot be fully explained by their diuretic effects. Here, we show that mice lacking the diuretic-sensitive Na+K+2Cl-cotransporter-1 Nkcc1 (Slc12a2) in insulin-secreting ß-cells of the pancreatic islet (Nkcc1ßKO) have reduced in vitro insulin responses to glucose. This is associated with islet hypoplasia at the expense of fewer and smaller ß-cells. Remarkably, Nkcc1ßKO mice excessively gain weight and progressive metabolic syndrome when fed a standard chow diet ad libitum. This is characterized by impaired hepatic insulin receptor activation and altered lipid metabolism. Indeed, overweight Nkcc1ßKO but not lean mice had fasting and fed hyperglycemia, hypertriglyceridemia and non-alcoholic steatohepatitis. Notably, fasting hyperinsulinemia was detected earlier than hyperglycemia, insulin resistance, glucose intolerance and increased hepatic de novo gluconeogenesis. Therefore, our data provide evidence supporting the novel hypothesis that primary ß-cell defects related to Nkcc1-regulated intracellular Cl-homeostasis and ß-cell growth can result in the development of metabolic syndrome shedding light into additional potential mechanisms whereby chronic diuretic use may have adverse effects on metabolic homeostasis in susceptible individuals.

Phospholipid membrane tubulation using ceramide doping "Cerosomes": Characterization and clinical application in psoriasis treatment.

Nanotechnology and material surface modification have provided a functional platform for the advancement of several medical fields such as dermatology. Furthermore, the smart choice of preparation material was proven to confer unique properties to the developed nanosystems. In this context, we focused on the sphingolipid "ceramide", whose deficiency was found to negatively affect psoriasis. Ceramide was doped into surfactant based vesicular phospholipid systems to create tubulated vesicles "cerosomes" loaded with a model anti-psoriatic drug "tazarotene", and their properties were tested as compared to ceramide free vesicles. Cerosomes were characterized for their drug entrapment, viscosity, in vitro drug release, morphology, ex vivo drug skin deposition, thermal behavior, and were clinically tested on psoriatic patients. The factorial design study revealed that the surfactant type, the ceramide: surfactant ratio, and the presence of ethanol in the hydration buffer affected the entrapment efficiency and the viscosity of the vesicles. Ceramide increased the entrapment of tazarotene, decreased its release while enhancing its deposition within the skin, correlating with better clinical therapeutic outcome compared to the topical marketed product. Ceramide was also able to cause significant membrane tubulation in the vesicles, causing them to deviate from the conventional spherical morphology. As a conclusion, cerosomes present a new functional treatment modality for psoriasis which is worthy of future experimentation.