The circadian clock in Health and Disease

 3D BMAL1-deficient HepG2 spheroid grown in Matrigel and stained with antibodies to HNF4a (red) and tubulin (green), as well as  DAPI nuclear stain (Baharan Fekry)

3D BMAL1-deficient HepG2 spheroid grown in Matrigel and stained with antibodies to HNF4a (red) and tubulin (green), as well as DAPI nuclear stain (Baharan Fekry)

 

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.) 

 
 
 Hematoxylin-eosin staining reveals hepatic micro- and macrovesicular steatosis (Aleix Ribas-Latre and Baharan Fekry)

Hematoxylin-eosin staining reveals hepatic micro- and macrovesicular steatosis (Aleix Ribas-Latre and Baharan Fekry)

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 nutrients intersect with the clock at the level of cellular metabolism. Nutrient challenge (such as occurs under conditions of high fat and high sucrose diet consumption) can reprogram the circadian clock in the liver (and potentially other tissues), however the mechanisms underlying this reprogramming are not known. Using in vitro and in vivo models, we are studying how food entrains the clock and what signaling mechanisms in liver, adipose tissue, and muscle are responsible for altered clock function in diet-induced obesity. We are also interested in the cross talk between metabolic tissues and the brain in metabolic disease, and the extent to which nutrients can alter circadian alignment across tissues. We are currently studying how insulin sensitizing agents can restore diet-induced changes in clock function. (We are grateful for the funding of this project by the NIH, NIDDK.) 

 24-hr. variance in the light exposure, wrist temperature, and activity of a human acquired via an actigraphy device (Condor Instruments)

24-hr. variance in the light exposure, wrist temperature, and activity of a human acquired via an actigraphy device (Condor Instruments)

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.