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

Abstract

Male mice lacking the Na+-K+-2Cl- cotransporter Slc12a2 (Nkcc1) specifically in insulin-secreting β-cells (Slc12a2βKO) have reduced β-cell mass and mild β-cell secretory dysfunction associated with overweight, glucose intolerance, insulin resistance, and metabolic abnormalities. Here, we confirmed and extended previous results to female Slc12a2βKO mice, which developed a similar metabolic syndrome-like phenotype as males, albeit milder. Notably, male and female Slc12a2βKO mice developed overweight without consuming excess calories. Analysis of the feeding microstructure revealed that young lean Slc12a2βKO male mice ate meals of higher caloric content and at a relatively lower frequency than normal mice, particularly during the night. In addition, overweight Slc12a2βKO 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 Slc12a2βKO mice. However, the time spent between meals remained intact in lean and overweight Slc12a2βKO 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 Slc12a2βKO 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.