Caloric restriction prevents obesity- and intermittent hypoxia-induced cardiac remodeling in leptin-deficient ob/ob mice.

Background: Intermittent hypoxia (IH), a key characteristic of obstructive sleep apnea, is independently associated with cardiometabolic impairment. While endogenous leptin levels may provide cardioprotective effects against hypoxia, leptin resistance is common among obese individuals presenting with obstructive sleep apnea. Methods: Here, we assessed left ventricle (LV) function using M-mode echocardiography in lean wild-type, calorically-restricted ob/ob, and obese ob/ob mice before and after 6 days of IH to determine how obesity and intermittent hypoxia interact to affect cardiac function independent of leptin signaling. Results: Calorically-restricting ob/ob mice for 4 weeks prior to IH exposure prevented weight gain (-2.1 ± 1.4 g) compared to free-fed ob/ob mice (8.7 ± 1.1 g). Free-fed ob/ob mice exhibited increased LV mass (0.713 ± 0.008 g) relative to wild-type mice (0.685 ± 0.004 g) and increased posterior wall thickness (0.089 ± 0.006 cm) relative to calorically-restricted ob/ob mice (0.072 ± 0.004 cm). Following 6 days of IH, free-fed ob/ob mice exhibited increases in cardiac output (44.81 ± 2.97 pre-IH vs. 57.14 ± 3.09 ml/min post-IH), LV diameter (0.400 ± 0.007 pre-IH vs. 0.428 ± 0.009 cm post-IH) and end diastolic volume (0.160 ± 0.007 pre-IH vs. 0.195 ± 0.012 ml post-IH) that were not detected in wild-type or calorically-restricted ob/ob mice. Conclusion: Caloric restriction can prevent obesity-induced LV hypertrophy and protect against acute IH-induced cardiac remodeling independent of leptin signaling. These findings may have clinical implications for obstructive sleep apnea.

The timing of intermittent hypoxia differentially affects macronutrient intake and energy substrate utilization in mice.

Sleep apnea is a common sleep disorder characterized by periodic breathing cessation and intermittent hypoxia (IH). Although previous studies have demonstrated that IH alone can influence metabolic outcomes such as body weight, it remains unclear how the timing of IH can specifically affect these outcomes. Here, we examine how pairing 10-h periods of IH to either the animals' resting phase (e.g., IH during the day) or active phase (e.g., IH during the night) differentially affects body weight, macronutrient selection, energy expenditure, respiratory exchange rate, and glucose tolerance. We find that in contrast to mice exposed to IH during the night, mice exposed to IH during the day preferentially decrease their carbohydrate intake and switch to fat metabolism. Moreover, when the IH stimulus was removed, mice that had been exposed to day IH continued to eat a minimal amount of carbohydrates and consumed a higher percentage of kilocalorie from fat for at least 5 days. These data demonstrate that food choice and substrate utilization are secondary to the timing of IH but not IH itself. Taken together, these data have key clinical implications for individuals with sleep apnea and particularly those who are also experiencing circadian disruption such as night-shift workers.NEW & NOTEWORTHY Pairing repeated hypoxic episodes to a mouse's resting phase during the day preferentially decreases carbohydrate intake and results in a switch to metabolic fat oxidation. These data indicate that the timing of intermittent hypoxia should be considered when calculating sleep apnea's effects on metabolic outcomes.

Bromocriptine improves glucose tolerance independent of circadian timing, prolactin, or the melanocortin-4 receptor.

Bromocriptine, a dopamine D2 receptor agonist originally used for the treatment of hyperprolactinemia, is largely successful in reducing hyperglycemia and improving glucose tolerance in type 2 diabetics. However, the mechanism behind bromocriptine's effect on glucose intolerance is unclear. Here, we tested three hypotheses, that bromocriptine may exert its effects on glucose metabolism by 1) decreasing prolactin secretion, 2) indirectly increasing activity of key melanocortin receptors in the central nervous system, or 3) improving/restoring circadian rhythms. Using a diet-induced obese (DIO) mouse model, we established that a 2-wk treatment of bromocriptine is robustly effective at improving glucose tolerance. We then demonstrated that bromocriptine is effective at improving the glucose tolerance of both DIO prolactin-deficient and melanocortin-4 receptor (MC4R)-deficient mice, pointing to bromocriptine's ability to affect glucose tolerance independently of prolactin or MC4R signaling. Finally, we tested bromocriptine's dependence on the circadian system by testing its effectiveness in environmental (e.g., repeated shifts to the light-dark cycle) and genetic (e.g., the Clock mutant mouse) models of circadian disruption. In both models of circadian disruption, bromocriptine was effective at improving glucose tolerance, indicating that a functional or well-aligned endogenous clock is not necessary for bromocriptine's effects on glucose metabolism. Taken together, these results do not support the role of prolactin, MC4R, or the circadian clock as integral to bromocriptine's underlying mechanism. Instead, we find that bromocriptine is a robust diabetic treatment and resilient to genetically induced obesity, diabetes, and circadian disruption.