Rabbit Anti-Human PER1 Polyclonal antibody

There are clear epidemiological associations between circadian disruption, obesity, and pathogenesis of type 2 diabetes. The mechanisms driving these associations are unclear. In the current study, we hypothesized that continuous exposure to constant light (LL) compromises pancreatic beta-cell functional and morphological adaption to diet-induced obesity leading to development of type 2 diabetes. To address this hypothesis, we studied wild type Sprague Dawley as well as Period-1 luciferase reporter transgenic rats (Per1-Luc) for 10 weeks under standard light-dark cycle (LD) or LL with concomitant ad libitum access to either standard chow or 60% high-fat diet (HFD). Exposure to HFD led to a comparable increase in food intake, body weight, and adiposity in both LD- and LL-treated rats. However, LL rats displayed profound loss of behavioral circadian rhythms as well as disrupted pancreatic islet clock function characterized by the impairment in the amplitude and the phase islet clock oscillations. Under LD cycle, HFD did not adversely alter diurnal glycemia, diurnal insulinemia, beta-cell secretory function as well as beta-cell survival, indicating successful adaptation to increased metabolic demand. In contrast, concomitant exposure to LL and HFD resulted in development of hyperglycemia characterized by loss of diurnal changes in insulin secretion, compromised beta-cell function, and induction of beta-cell apoptosis. This study suggests that circadian disruption and diet-induced obesity synergize to promote development of beta-cell failure, likely mediated as a consequence of impaired islet clock function.

The mammalian circadian clock is an endogenous biological timer comprised of transcriptional/translational feedback loops of clock genes. Bmal1 encodes an indispensable transcription factor for the generation of circadian rhythms. Here, we report a new circadian mutant mouse from gene-trapped embryonic stem cells harboring a C-terminus truncated Bmal1 (Bmal1(GT Delta C)) allele. The homozygous mutant (Bmal1(GT Delta C/GT Delta C)) mice immediately lost circadian behavioral rhythms under constant darkness. The heterozygous (Bmal1(+/GT Delta C)) mice displayed a gradual loss of rhythms, in contrast to Bmal1+/-mice where rhythms were sustained. Bmal1(GT Delta C/GT Delta C) mice also showed arrhythmic mRNA and protein expression in the SCN and liver. Lack of circadian reporter oscillation was also observed in cultured fibroblast cells, indicating that the arrhythmicity of Bmal1(GT Delta C/GT Delta C) mice resulted from impaired molecular clock machinery. Expression of clock genes exhibited distinct responses to the mutant allele in Bmal1(+/GT Delta C) and Bmal1(GT Delta C/GT Delta C) mice. Despite normal cellular localization and heterodimerization with CLOCK, overexpressed BMAL1(GT Delta C) was unable to activate transcription of Per1 promoter and BMAL1-dependent CLOCK degradation. These results indicate that the C-terminal region of Bmal1 has pivotal roles in the regulation of circadian rhythms and the Bmal1(GT Delta C) mice constitute a novel model system to evaluate circadian functional mechanism of BMAL1.