The circadian clock in Health and Disease

The circadian clock in cancer

There is evidence that circadian disruption increases the risk of acquiring several types of cancer. Recently, it was found that mimicking human jet lag in mice is sufficient to induce spontaneous hepatocellular carcinoma (HCC). We are interested in how the expression and activity of specific nuclear receptors in the liver are altered in the context of HCC. We have recently discovered that an isoform of hepatocyte nuclear factor 4 alpha (Hnf4a) that is expressed in HCC downregulates the circadian clock protein BMAL1. Using a combination of in vitro and in vivo models, we have shown that ectopic expression of BMAL1 prevents tumor growth. Using strategies which are thought to increase circadian robustness, we are trying to determine whether circadian targeting of Hnf4a-positive HCC might be a tractable method to treat these tumors. (We are grateful for the funding of this project by the American Cancer Society.) 

The circadian clock in Metabolic disease

Circadian disruption increases the risk for metabolic diseases, including obesity and type II diabetes. Nutrient challenge itself can interfere with normal clock function, a process that is thought to occur early and be involved in the progression of metabolic disease. Food intake is a strong driver of the circadian clock in some tissues such as the liver. We are interested in understanding how nutrient intake intersects with the clock at the level of cellular metabolism. Projects centered on the links between circadian rhythms and metabolic disease include: 1) understanding the mechanisms by which circadian clock genes and energy intake control the diurnal proliferation of adipocyte progenitors cells of white adipose tissue; 2) understanding the relationship between impaired clock function and insulin resistance in insulin-sensitive tissues; and 3) understanding the origin of 24-h. rhythms within the paraventricular nucleus, and how they drive rhythmic energy intake and energy balance. (We are grateful for the funding of these projects by the NIH, NIDDK.) 

The circadian clock in Metabolic disease

Individuals who have undergone weight loss surgery often report better sleep following surgery. Several reasons for this have been proposed. We hope to understand whether chronotype is associated with sleep improvement following weight loss surgery and to determine whether there is an association between weight loss following surgery and chronotype. To this end, we are embarking on actigraphy analysis to longitudinally assess the diurnal patterns of obese individuals who undergo gastric bypass surgery.