A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.

http://science.sciencemag.org/content/sci/354/6315/1008.full.pdf

Circadian physiology of metabolism.

https://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30250-9.pdf

Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan

Meal Timing Regulates the Human Circadian System

Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered "metabolically healthy." However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO - specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.

/pdf/metabolically-healthy-obesity-facts-and-fantasies-1jarb4cqvj.pdf

Metabolically healthy obesity: facts and fantasies.

Feeding, which is essential for all animals, is regulated by homeostatic mechanisms. In addition, food consumption is temporally coordinated by the brain over the circadian (~24 h) cycle. A network of circadian clocks set daily windows during which food consumption can occur. These daily windows mostly overlap with the active phase. Brain clocks that ensure the circadian control of food intake include a master light-entrainable clock in the suprachiasmatic nuclei of the hypothalamus and secondary clocks in hypothalamic and brainstem regions. Metabolic hormones, circulating nutrients and visceral neural inputs transmit rhythmic cues that permit (via close and reciprocal molecular interactions that link metabolic processes and circadian clockwork) brain and peripheral organs to be synchronized to feeding time. As a consequence of these complex interactions, growing evidence shows that chronodisruption and mistimed eating have deleterious effects on metabolic health. Conversely, eating, even eating an unbalanced diet, during the normal active phase reduces metabolic disturbances. Therefore, in addition to energy intake and dietary composition, appropriately timed meal patterns are critical to prevent circadian desynchronization and limit metabolic risks. This Review provides insight into the dual modulation of food intake by homeostatic and circadian processes, describes the mechanisms regulating feeding time and highlights the beneficial effects of correctly timed eating, as opposed to the negative metabolic consequences of mistimed eating. In this Review, Etienne Challet discusses the dual modulation of food intake by homeostatic and circadian processes, describes the mechanisms regulating feeding time and highlights the beneficial effects of correctly timed eating, as opposed to the negative metabolic consequences of mistimed eating.

The circadian regulation of food intake.

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.

/pdf/impact-of-sleep-and-circadian-disruption-on-energy-balance-5301hs2xb1.pdf

Michael J. Joyner

Papers

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions.