The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.

The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior and metabolism with the solar cycle. Genetic or environmental perturbation of circadian cycles contributes to metabolic disorders including type 2 diabetes. To study the impact of the cell-autonomous clock on pancreatic β-cell function, we examined islets from mice with either intact or disrupted BMAL1 expression both throughout life and limited to adulthood. We found pronounced oscillation of insulin secretion that was synchronized with the expression of genes encoding secretory machinery and signaling factors that regulate insulin release. CLOCK/BMAL1 co-localized with the pancreatic transcription factor PDX1 within active enhancers distinct from those controlling rhythmic metabolic gene networks in liver. β-cell clock ablation in adult mice caused severe glucose intolerance. Thus cell-type specific enhancers underlie the circadian control of peripheral metabolism throughout life and may help explain its deregulation in diabetes.

Despite the importance of precipitation and moisture transport over the Tibetan Plateau for glacier mass balance, river runoff and local ecology, changes in these quantities remain highly uncertain and poorly understood. Here we use observational data and model simulations to explore the close relationship between summer rainfall variability over the southwestern Tibetan Plateau (SWTP) and that over central-eastern India (CEI), which exists despite the separation of these two regions by the Himalayas. We show that this relationship is maintained primarily by ‘up-and-over' moisture transport, in which hydrometeors and moisture are lifted by convective storms over CEI and the Himalayan foothills and then swept over the SWTP by the mid-tropospheric circulation, rather than by upslope flow over the Himalayas. Sensitivity simulations confirm the importance of up-and-over transport at event scales, and an objective storm classification indicates that this pathway accounts for approximately half of total summer rainfall over the SWTP.

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The present work describes, for the first time, the use of a new and strong complexing agent, ethylenediamine-N,N'-disuccinic acid (EDDS) in the homogeneous Fenton process. The effect of H(2)O(2) concentration, Fe(III)-EDDS concentration, pH value, and oxygen concentration on the homogeneous Fenton degradation of bisphenol A (BPA) used as a model pollutant, was investigated. Surprisingly, the performance of BPA oxidation in an EDDS-driven Fenton reaction was found to be much higher at near neutral or basic pH than at acidic pH. Inhibition and probe studies were conducted to ascertain the role of several radicals (e.g., (•)OH, HO(2)(•)/O(2)(•-)) on BPA degradation. This unexpected effect of pH on Fenton reaction efficiency could be due to the formation of HO(2)(•) or O(2)(•-) radicals and to the presence of different forms of the complex Fe(III)-EDDS as a function of pH. Indeed, the reduction of Fe(III)-EDDS to Fe(II)-EDDS is a crucial step that governs the formation of hydroxyl radical, mainly responsible for BPA degradation. In addition to its ability to maintain iron in soluble form, EDDS acts as a superoxide radical-promoting agent, enhancing the generation of Fe(II) (the rate limiting step) and therefore the production of (•)OH radicals. These results are very promising because they offer an important new treatment option at higher range of pH values and more particularly at pHs encountered in natural conditions.