Humans adapt to the 24-hour day produced by the earth rotating on its axis. This internally-driven 24-hour (or, ?circadian?) adaptation in mammals produces rhythmicity in sleep, food intake, body temperature, and hormone secretion, among other biological processes. The circadian clock exists in all cells and is heavily influenced by zeitgebers (or, ?time-givers?) such as food and light. Epidemiological studies reveal that environmentally- or genetically-induced perturbation of our circadian clock leads to metabolic disease, in part by misaligning the central clock in the brain with peripheral clocks. Nutrient challenge, such as high fat diet feeding, can reprogram the liver circadian clock in a manner that misaligns it from the brain. The experiments of this proposal are designed to test the hypothesis that high fat diet-induced circadian reprogramming is accomplished by improper recruitment of the circadian protein BMAL1, in an insulin-dependent manner. A high fat diet, which produces insulin resistance in the liver long term, will be used to address the mechanisms underlying hepatic reprogramming. In particular, we will study the localization and chromosomal recruitment of a key circadian transcriptional activator, the BMAL1 protein, under conditions of high fat feeding. BMAL1 protein is necessary for cellular 24-hour rhythmicity but under high fat diet feeding, it gets recruited inappropriately to DNA, altering 24-hour rhythmicity in target gene expression and subsequent circadian metabolism in the liver. The mechanisms underlying this disrupted recruitment are not known but our preliminary data suggest that altered BMAL1 recruitment may be a result of hepatic insulin resistance, as BMAL1 chromatin recruitment and target gene expression are restored by the application of the anti-diabetic thiazolidinediones. Secondly, the hypothesis that insulin signaling is the primary driver of hepatic circadian reprogramming will be tested by using a combination of insulin resistant rodent models as well as by a class of insulin-sensitizing drugs. These experiments will rely heavily on biochemical and bioinformatics approaches. Rodents which lack the insulin receptor (a model of complete hepatic insulin resistance) will be analyzed in the absence of high fat feeding for changes in BMAL1 recruitment as well as changes in chromosomal architecture at BMAL1 target DNA. In addition, administration of the insulin-sensitizing drugs, the Thiazolidinediones, commonly used in humans will determine whether high fat diet-induced circadian reprogramming is insulin- dependent. Collectively, these models will reveal whether hepatic insulin resistance is necessary or sufficient for diet-induced circadian reprogramming in the liver. These results will have important implications for how other insulin-sensitive tissues respond to diet and the extent to which diet may control metabolic homeostasis through synchrony of peripheral and central circadian clocks.
Disruption of our 24-hour (?circadian?) clock leads to metabolic diseases including obesity and insulin resistance. Nutrients are a primary driver of peripheral circadian clocks and when nutrient input timing or quality is disrupted, peripheral clocks are compromised. The proposed experiments are designed to understand the mechanisms underlying diet-induced circadian control and the extent to which it depends on alterations in insulin signaling and sensitivity.
|Fekry, Baharan; Ribas-Latre, Aleix; Baumgartner, Corrine et al. (2018) Incompatibility of the circadian protein BMAL1 and HNF4? in hepatocellular carcinoma. Nat Commun 9:4349|