Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease.

The assembly of primary cilia is dependent on intraflagellar transport (IFT), which mediates the bidirectional movement of proteins between the base and tip of the cilium. In mice, congenic mutations disrupting genes required for IFT (e.g., Tg737 or the IFT kinesin Kif3a) are embryonic lethal, whereas kidney-specific disruption of IFT results in severe, rapidly progressing cystic pathology. Although the function of primary cilia in most tissues is unknown, in the kidney they are mechanosenstive organelles that detect fluid flow through the tubule lumen. The loss of this flow-induced signaling pathway is thought to be a major contributing factor to cyst formation. Recent data also suggest that there is a connection between ciliary dysfunction and obesity as evidenced by the discovery that proteins associated with human obesity syndromes such as Alström and Bardet-Biedl localize to this organelle. To more directly assess the importance of cilia in postnatal life, we utilized conditional alleles of two ciliogenic genes (Tg737 and Kif3a) to systemically induce cilia loss in adults. Surprisingly, the cystic kidney pathology in these mutants is dependent on the time at which cilia loss was induced, suggesting that cyst formation is not simply caused by impaired mechanosensation. In addition to the cystic pathology, the conditional cilia mutant mice become obese, are hyperphagic, and have elevated levels of serum insulin, glucose, and leptin. We further defined where in the body cilia are required for normal energy homeostasis by disrupting cilia on neurons throughout the central nervous system and on pro-opiomelanocortin-expressing cells in the hypothalamus, both of which resulted in obesity. These data establish that neuronal cilia function in a pathway regulating satiety responses.

Effect of dairy supplementation on body composition and insulin resistance in mice.

OBJECTIVE: This study examined whether yogurt supplementation attenuated the weight gain and insulin resistance in mice fed a moderate-fat diet. METHODS: Nine-week-old male mice (F1 BTBR x C57Bl6/J) were housed individually for the duration of the study. After initial measurements of body weight and composition, mice were randomly assigned to receive one of two isocaloric diets (19.4% kcal protein, 45.5% kcal carbohydrate, and 35.1% kcal fat). One diet was supplemented with dried yogurt powder (10.75 g/100 g of diet). In the first experiment, mice received the diets for 4 wk, after which body weight and body composition were reassessed. In the second experiment, an insulin tolerance test was performed at week 4 and glucose uptake in gonadal fat was assessed at week 5. RESULTS: Baseline body weight was not significantly different between control and yogurt mice (P = 0.85). Body weight and fat mass increased significantly over time (P < 0.001) and there was a significant effect of diet on the increase in body weight (P < 0.05) and fat mass (P < 0.001), with the yogurt mice gaining less weight and fat than the control mice. Food intake was not significantly affected by the yogurt supplementation (P = 0.906). Digestive efficiency was significantly lower in the yogurt mice (P < 0.05) due to greater fecal production (P < 0.01). There was no significant effect of diet on the glucose area under the curve during the insulin tolerance test (P = 0.24). Glucose uptake in the gonadal fat was significantly higher in the yogurt mice than in controls under basal (P < 0.05) and insulin-stimulated (P < 0.05) conditions. CONCLUSION: Yogurt supplementation resulted in less weight and fat gain in mice fed isocaloric diets due to a decrease in digestive efficiency. Yogurt also enhanced the uptake of glucose in fat but did not significantly improve insulin sensitivity.