Molecular Metabolism最新文献

Objectives: Oxytocin (OT) is a neuropeptide produced in the paraventricular (PVH) and supraoptic (SON) nuclei of the hypothalamus. Either peripheral or central OT administration reduces food intake through reductions in meal size. However, pharmacological approaches do not differentiate whether OT's influence on food intake is mediated by OT neurons located in the PVH vs. the SON. Here we address this gap using both gain- and loss-of-function approaches targeting OT neurons.

Methods: OT neuron-specific designer receptors exclusively activated by designer drugs (DREADDs) were targeted in either the PVH or SON in rats, thus allowing for evaluation of caloric intake following selective activation of OT neurons separately in each nucleus. To examine the physiological role of distinct OT neuron populations in eating behavior, a viral-mediated approach was used to silence synaptic transmission of OT neurons separately in either the PVH or SON.

Results: DREADDs-mediated excitation of PVH OT neurons reduced consumption of standard chow via reductions in meal size. On the contrary, SON OT neuron activation had the opposite effect by increasing standard chow consumption. Consistent with these opposing outcomes, activation of PVH and SON OT neurons simultaneously had minimal effects on food intake. Additional results from chronic loss-of-function experiments reveal that PVH OT neuron silencing significantly increased consumption of a high fat and high sugar diet by increasing meal size whereas SON OT neuron silencing reduced chow consumption by decreasing meal size.

Conclusions: Collectively these findings suggest that PVH and SON OT neurons differentially modulate food intake by either reducing or increasing caloric consumption, respectively.

Objective: The circadian clock anticipates daily repetitive events to adapt physiological processes. In mammals, the circadian system consists of a master clock in the suprachiasmatic nucleus (SCN), which synchronizes subordinate tissue clocks, including extra-SCN central nervous system (CNS) clocks involved in functions such as sleep and appetite regulation. Appetite is controlled by both homeostatic and non-homeostatic (hedonic) circuits. Homeostatic appetite addresses energy needs, while hedonic feeding targets cravings for palatable, calorie-dense foods. The adipokine leptin is a major appetite regulator, interacting with the circadian clock. Although leptin's role in satiation through its action in the mediobasal hypothalamus (MBH) is well established, its involvement in the circadian regulation of feeding remains poorly understood. We hypothesized that circadian gating of leptin signaling in the CNS controls homeostatic and hedonic appetite across the day.

Methods: We analyzed food intake rhythms in mice with a loss of leptin (ob/ob mice) or clock function (Per1/2 or Bmal1 KO) and in mice with specific disruption of leptin circadian gating in the CNS (ObRb.Bmal1).

Results: We found that in leptin-deficient mice hedonic appetite increases specifically in the early rest phase. In contrast, clock-deficient Per1/2 mutant mice exhibit blunted rhythms in both hedonic and homeostatic appetite control. Finally, when clock function is disrupted in leptin-sensitive neurons only, mice display a lower sensitivity to palatable food, along with reduced initial weight gain and adipose hypertrophy under obesogenic diet conditions.

Conclusions: Our data describe a local clock-controlled central leptin gating mechanism that modulates hedonic food intake rhythms and impacts metabolic homeostasis.