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Student feature: Uncovering the role of circadian rhythms in obesity

February 17, 2020
Rachel Van Drunen, GSBS student

This article was written by student Rachel Van Drunen, the third place winner of the 2019 Annual Report Science Writing Contest. Van Drunen is a PhD student with the Program in Neuroscience and her advisor is Kristin L. Eckel-Mahan, PhD.

We’ve all found ourselves up late at night on that JUST-ONE-MORE-EPISODE binge of a must-watch Netflix series when it hits — you’re hungry. You go into the pantry, pull out a large bag of your favorite midnight snack, sit back down, press play, and before you know it you’ve emptied at least half the bag, if not more. You wonder what caused you to suddenly venture out of your cozy encampment in your bed and pilfer the pantry for snacks, especially when you’ve already had your regular three daily meals. You wonder why you keep snacking, almost absent mindedly, when you only intended to eat a few bites. Now imagine doing the same excessive eating throughout the day as well. For individuals who suffer from obesity, this is a major challenge in their daily living.

Van Drunen YIR photo 1

Obesity is a growing worldwide epidemic with over 650 million clinically obese people in 2016. While many factors contribute to inordinate weight gain, the dysregulation of the mechanisms controlling feeding and metabolism is the main underlying cause. In the past decade, growing evidence suggest that an individual’s circadian rhythmicity plays a significant role in their regulation or dysregulation of feeding and metabolism. This means that the time of day an individual chooses to eat plays an essential role in their overall health. To clarify how these two factors – the time of day and eating – are interlinked, we first need to define circadian rhythms.

From bacteria to plants to humans, nearly all of Earth’s organisms have some form of biological clock in each cell synchronized by external environmental cues. As best described by Salk Institute researcher Satchin Panda, PhD, in a 2018 New York Times interview: “We’re designed to have 24-hour rhythms in our physiology and metabolism. These rhythms exist because, just like our brains need to go to sleep each night to repair, reset, and rejuvenate, every organ needs to have down time to repair and reset as well.”

The rising and setting of the sun is the strongest entrainer of our circadian clock. Therefore, when we disrupt our internal clock, whether by jet lag, shift work, or late nights of binge watching, we see corresponding changes in our physiology. Two populations which substantiate the importance of circadian health are shift workers and individuals who are chronically jet lagged. In both populations, the risk for developing diseases like obesity, cancer, and heart disease are all increased. In one study investigating the effects of late nights, adults were asked to shift their normal sleeping and waking up time back by a few hours for 10 consecutive days. Over the course of the 10 days, their eating patterns diverged from their norm and their blood pressure increased while their insulin and blood sugar control was impaired (Scheer et al., 2009). These changes in physiology underscore the importance of circadian rhythms in eating and metabolism, leading us to consider at the biological level how one may lead to the other.

The dynamic time dependent nature of feeding and metabolic balance have only recently become factored into experimental designs. Our laboratory focuses on this linkage between circadian rhythms and feeding and metabolism to study how the disruption of these rhythmic regulations can promote obesity. My PhD work specifically focuses on the neuronal aspect of feeding and metabolism regulation in the circadian context. A crucial brain region I focus on is the hypothalamus — a small region on the underside of the brain, which is an essential receiver and integrator of nutrient information and signaling. The neurons in this area are divided into smaller subsets known as hypothalamic nuclei, which each help to determine whether or not you should eat the rest of that bag of chips. My research focuses on two of these nuclei, the arcuate nucleus (ARC), which receives nutrient information from the bloodstream, and the paraventricular nucleus (PVN), which communicates the information from the ARC via neural signaling, helping to modulate food intake.

Van Drunen YIR photo 2

To study the circadian regulation of these neuronal subpopulations in the hypothalamus and their effect on eating and metabolism, I use a variety of neuroscience and biochemistry techniques. One model I study is a mouse model lacking circadian rhythms in the PVN. These mice have their core clock gene known as Bmal1 (Brain and muscle ARNTL1 like protein 1) deleted. Bmal1 is an essential gene present in all cells that have circadian rhythms. By injecting a genetically altered virus into the target tissue, in this case the PVN of the mouse, researchers can selectively target and delete Bmal1 in the tissue which the virus is injected. Following this procedure, my lab has examined the behavioral changes in the mouse, looking at its activity, feeding frequency, quantity of food intake, and body weight gain. We saw increases in each of these areas, which suggested patterns of overeating, irregular eating and activity, and metabolic inefficiency arise after the circadian rhythms in the PVN were deleted. Seeing these changes is exciting as they support the idea that the circadian clock in the PVN rhythmically regulates eating and metabolism.

In short, when circadian clocks are all synchronized, they can be your best friend in health and wellbeing; however, when disrupted, they can be your worst enemy. We think studying how to resynchronize these internal clocks is key to restoring one’s health. We hope to continue fleshing out what we know about the feeding and metabolism circuit by examining, at the molecular level, the targets of Bmal1 activity. At the cellular level, we will identify the neuron subtypes involved; while at the behavior level, food intake, activity, and body weight will be the final checkpoint to illustrate the link between obesity and desynchronized circadian rhythms. In the long term, our goal is to uncover novel molecular and cellular targets involved in the rhythmic regulation of feeding and metabolism, which can be used for treating obesity.

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