Endocrinology. 2019 Jul 05. pii: en.2018-00935. [Epub ahead of print]
Recent evidence suggests that the circadian timing system plays a role in energy and glucose homeostasis, and disruptions to this system are a risk factor for the development of metabolic disorders. We exposed animals to a constantly shifting lighting environment comprised of a 6-hour advance, occurring every 6 days, to chronically disrupt their circadian timing system. This treatment caused a gradual increase in body weight of 12 ± 2% after 12 phase shifts compared with a 6 ± 1% increase in mice under control lighting conditions. Additionally, following the 5th phase shift, light cycle-disrupted animals showed a reversal in their diurnal pattern of energy homeostasis and locomotor activity followed by a subsequent loss of this rhythm. To investigate potential molecular mechanisms mediating these metabolic alterations, we assessed central leptin and insulin sensitivity. We discovered that light cycle-disrupted mice had a decrease in central leptin signalling, as indicated by a reduction in the number of phosphorylated STAT3 immunoreactive cells in the arcuate nucleus of the hypothalamus. Furthermore, light cycle-disrupted animals exhibited a marked increase in fasting blood glucose (269.4 ± 21.1 mg/dl), compared with controls (108.8 ± 21.3 mg/dl). This dramatic increase in fasting glucose levels was not associated with an increase in insulin levels suggesting impairments in pancreatic insulin release. Peripheral hyperglycaemia was accompanied by central alterations in insulin signalling at the level of pAkt and IRS1, suggesting that light cycle-disruption alters central insulin signalling. These results provide mechanistic insights into the association between light cycle-disruption and metabolic disease.