Circadian rhythm disturbances are observed in, e.g., aging and neurodegenerative diseases and are associated with an increased incidence of obesity and diabetes. We subjected male C57Bl/6J mice to constant light [12-h light-light (LL) cycle] to examine the effects of a disturbed circadian rhythm on energy metabolism and insulin sensitivity. In vivo electrophysiological recordings in the central pacemaker of the suprachiasmatic nuclei (SCN) revealed an immediate reduction in rhythm amplitude, stabilizing at 44% of normal amplitude values after 4 d LL. Food intake was increased (+26%) and energy expenditure decreased (-13%), and we observed immediate body weight gain (d 4: +2.4%, d 14: +5.0%). Mixed model analysis revealed that weight gain developed more rapidly in response to LL as compared to high fat. After 4 wk in LL, the circadian pattern in feeding and energy expenditure was completely lost, despite continuing low-amplitude rhythms in the SCN and in behavior, whereas weight gain had stabilized. Hyperinsulinemic-euglycemic clamp analysis revealed complete abolishment of normal circadian variation in insulin sensitivity in LL. In conclusion, a reduction in amplitude of the SCN, to values previously observed in aged mice, is sufficient to induce a complete loss of circadian rhythms in energy metabolism and insulin sensitivity.

Disruption of circadian rhythmicity is associated with obesity and related disorders, including type 2 diabetes and cardiovascular disease. Specifically, prolonged artificial light exposure associates with obesity in humans, although the underlying mechanism is unclear. Here, we report that increasing the daily hours of light exposure increases body adiposity through attenuation of brown adipose tissue (BAT) activity, a major contributor of energy expenditure. Mice exposed to a prolonged day length of 16-and 24-h light, compared with regular 12-h light, showed increased adiposity without affecting food intake or locomotor activity. Mechanistically, we demonstrated that prolonged day length decreases sympathetic input into BAT and reduces β3-adrenergic intracellular signaling. Concomitantly, prolonging day length decreased the uptake of fatty acids from triglyceride-rich lipoproteins, as well as of glucose from plasma selectively by BAT. We conclude that impaired BAT activity is an important mediator in the association between disturbed circadian rhythm and adiposity, and anticipate that activation of BAT may overcome the adverse metabolic consequences of disturbed circadian rhythmicity. M odern world society is subjected to disturbances of circadian rhythms by shift work, sleep deprivation, and environmental light pollution. Importantly, the increasing prevalence of obesity is associated with a disrupted sleep-wake pattern in humans (1) and coincides with the availability of artificial light (2, 3). Additionally, a recent study revealed a relationship between exposure to light at night and obesity in a cross-sectional analysis of over 100,000 women (4). Light input is the most important cue for generation of circadian (∼24 h) rhythms by the master clock. Both in rodents and humans the master clock is situated in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is responsible for synchronization of peripheral clocks throughout the body, which is mediated by endocrine and neuronal signals (5). A causal role for a disturbed circadian rhythm in the development of obesity has been demonstrated by animal studies. Mice with genetically dysfunctional clock genes develop obesity and insulin resistance (6-9). Moreover, specific ablation of the SCN induces acute weight gain (10). These results indicate a crucial role for the SCN in the regulation of adiposity.Interestingly, we previously showed that prolonged light exposure only is sufficient to enhance weight gain in mice. Constant light disrupts the central circadian clock, evidenced by an immediate reduction in the circadian amplitude of SCN electrical activity. Moreover, constant light induces body weight gain and insulin resistance, even faster than high-fat diet, which was not caused by increased food intake or reduced locomotor activity (11). Therefore, disruption of the central biological clock likely induces weight gain by decreasing energy expenditure.Recently, it has been recognized that brown adipose tissue (BAT) importantly contributes to energy ...

Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized with the light/dark cycle. Highest uptake was found at the onset of the active period, which coincided with high lipoprotein lipase expression and low angiopoietin-like 4 expression by BAT. Diurnal rhythmicity in BAT activity determined the rate at which lipids were cleared from the circulation, thereby imposing the daily rhythm in plasma lipid concentrations. In mice as well as humans, postprandial lipid excursions were nearly absent at waking. We anticipate that diurnal BAT activity is an important factor to consider when studying the therapeutic potential of promoting BAT activity.

BackgroundCataract and glaucoma are the major causes of blindness in Nepal. Bhaktapur is one of the three districts of Kathmandu valley which represents a metropolitan city with a predominantly agrarian rural periphery. This study was undertaken to determine the prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma among subjects residing in this district of Nepal.MethodsSubjects aged 40 years and above was selected using a cluster sampling methodology and a door to door enumeration was conducted for a population based cross sectional study. During the community field work, 11499 subjects underwent a structured interview regarding awareness (heard of) and knowledge (understanding of the disease) of cataract and glaucoma. At the base hospital 4003 out of 4800 (83.39%) subjects underwent a detailed ocular examination including log MAR visual acuity, refraction, applanation tonometry, cataract grading (LOCSΙΙ), retinal examination and SITA standard perimetry when indicated.ResultsThe age-sex adjusted prevalence of blindness (best corrected <3/60) and low vision (best corrected <6/18 ≥3/60) was 0.43% (95%C.I. 0.25 - 0.68) and 3.97% (95% C.I. 3.40 - 4.60) respectively. Cataract (53.3%) was the principal cause of blindness. The leading causes of low vision were cataract (60.8%) followed by refractive error (12%). The cataract surgical coverage was 90.36% and was higher in the younger age group, females and illiterate subjects. Pseudophakia was seen in 94%. Awareness of cataract (6.7%) and glaucoma (2.4%) was very low. Among subjects who were aware, 70.4% had knowledge of cataract and 45.5% of glaucoma. Cataract was commonly known to be a 'pearl like dot' white opacity in the eye while glaucoma was known to cause blindness. Awareness remained unchanged in different age groups for cataract while for glaucoma there was an increase in awareness with age. Women were significantly less aware (odds ratio (OR): 0.63; 95%, confidence interval (CI): 0.54 - 0.74) for cataract and (OR: 0.64; 95% CI: 0.50 - 0.81) for glaucoma. Literacy was also correlated with awareness.ConclusionThe low prevalence of visual impairment and the high cataract surgical coverage suggests that cataract intervention programs have been successful in Bhaktapur. Awareness and knowledge of cataract and glaucoma was very poor among this population. Eye care programs needs to be directed towards preventing visual impairment from refractive errors, screening for incurable chronic eye diseases and promoting health education in order to raise awareness on cataract and glaucoma among this population.

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3‐Leiden.CETP mice to either regular light‐dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light‐dark cycles (12 hours shifts), as a well‐established model for shift work. We found that mice exposed to 15 weeks of alternating light‐dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light‐dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light‐dark cycles directly aggravates atherosclerosis development.

The presence and distribution of misrouted (MR) olfactory projection fibres were studied in the olfactory bulbs of control human brains and in the brains of people who had suffered from Parkinson's and Alzheimer's disease. It appeared that MR fibres, that is, fibres that terminate deep into the glomerular layer, are a common phenomenon in the bulbs of aged people. In all but one of the bulbs studied, MR fibres are present. The amount of MR fibres is not related to age. With a few exceptions, the MR fibres are restricted to the external plexiform layer (EPL). Only in Parkinson bulbs the MR fibres occasionally form glomerulus-like structures. These pseudo glomeruli are located in the EPL. It is concluded that MR olfactory projection fibres are a normal phenomenon in the human olfactory bulb. In nonhuman mammalians, MR fibres have only been observed in foetal and neonatal olfactory bulbs. Possibly, the age-related loss of mitral cells, which are the natural synaptic targets for the olfactory projection fibres, may play a role in the aberrant behaviour of the MR olfactory receptor cell axons. The ectopic glomerulus-like structures in Parkinson bulbs share some characteristics with normal rat glomeruli that are not observed in normal human olfactory glomeruli. This may refer to possible changes in the genetic content of olfactory structures in Parkinson patients.

We have previously shown that acute sleep curtailment induces insulin resistance, both in healthy individuals as well as in patients with type 1 diabetes, suggesting a causal role for sleep disturbances in pathogenesis of insulin resistance, independent of endogenous insulin production. However, the underlying mechanisms remain unclear. This study aimed to explore the metabolic pathways affected by sleep loss using targeted metabolomics in human fasting plasma samples. Healthy individuals (n = 9) and patients with type 1 diabetes (n = 7) were studied after a single night of short sleep (4 h) versus normal sleep (8 h) in a cross-over design. Strikingly, one night of short sleep specifically increased the plasma levels of acylcarnitines, essential intermediates in mitochondrial fatty acid oxidation (FAO). Specifically, short sleep increased plasma levels of tetradecenoyl-l-carnitine (C14:1) (+32%, p = 2.67*10(-4)), octadecanoyl-l-carnitine (C18:1) (+22%, p = 1.92*10(-4)) and octadecadienyl-l-carnitine (C18:2) (+27%, p = 1.32*10(-4)). Since increased plasma acylcarnitine levels could be a sign of disturbed FAO, it is possible that sleep curtailment acutely induces inefficient mitochondrial function. Our observations provide a basis for further research into the role of acylcarnitines as a potential mechanistic pathway by which sleep deprivation - even short term - causes adverse metabolic effects, such as insulin resistance.

Disturbance of the circadian clock has been associated with increased risk of cardio-metabolic disorders. Previous studies showed that optimal timing of food intake can improve metabolic health. We hypothesized that time-restricted feeding could be a strategy to minimize long term adverse metabolic health effects of shift work and jetlag. In this study, we exposed female FVB mice to weekly alternating light-dark cycles ( i . e . 12 h shifts) combined with ad libitum feeding, dark phase feeding or feeding at a fixed clock time, in the original dark phase. In contrast to our expectations, long-term disturbance of the circadian clock had only modest effects on metabolic parameters. Mice fed at a fixed time showed a delayed adaptation compared to ad libitum fed animals, in terms of the similarity in 24 h rhythm of core body temperature, in weeks when food was only available in the light phase. This was accompanied by increased plasma triglyceride levels and decreased energy expenditure, indicating a less favorable metabolic state. On the other hand, dark phase feeding accelerated adaptation of core body temperature and activity rhythms, however, did not improve the metabolic state of animals compared to ad libitum feeding. Taken together, restricting food intake to the active dark phase enhanced adaptation to shifts in the light-dark schedule, without significantly affecting metabolic parameters.