Setting the metabolic clock: integrating circadian and homeostatic pathways in the mediobasal hypothalamus

Every day we must balance the internal needs of our body such as hunger and sleep with external demands such as varying availability of food, daylight etc. To cope with these varying challenges, an ancient part of our brain called the hypothalamus has evolved to contain internal 24h biological clocks that anticipate daily changes in the external world such that we are prepared for events such as sunrise and sunset. The hypothalamus has also evolved mechanisms that function like a thermostat to detect and act to correct imbalances in the body's energy and fluid levels. Unfortunately we do not know how the daily clock and homeostatic influences are combined and communicated by hypothalamic brain cells. In this proposal, we will use new technologies to monitor the electrical activity of hypothalamic brain cells and determine how daily clock and homeostatic influences are incorporated by these cells and how they respond to changes in the external world. Importantly, this research will also advance our understanding of how modern 24hr lifestyles (chronic shift work, jet lag, sleep deprivation) may be contributing to human diseases, such as metabolic syndrome.

To adapt to varying internal and external conditions, all living life forms have evolved daily or circadian clocks as well as homeostatic mechanisms. Disruption of these essential intrinsic processes negatively affects health and well-being and can shorten lifespan. Both circadian and homeostatic mechanisms are present in the mediobasal hypothalamus (MBH), a brain structure of key importance in the regulation of energy balance, reproduction, and body temperature. In preliminary research, we have found that MBH neurons expressing circadian clock genes show electrical properties that are similar to those of the main circadian clock in the suprachiasmatic nuclei. These putative clock neurons are responsive to energy balance cues such as leptin, and glucose, but it is unclear how they integrate these cues with the circadian clock or how they interact and communicate with other neurons present in the MBH. Using a new brain slice preparation in which circadian and homeostatic influences on the electrical activity of many MBH neurons can be simultaneously monitored, we aim to address these important questions.

The research questions posed within this proposal are of major interest to ACADEMIC GROUPINGS in Biological and BioMedical Sciences. The academic community will benefit from elucidation of novel mechanisms whereby circadian and homeostatic pathways integrate which the hypothalamus to dictate feeding behaviour and energy balance. Understanding the neural basis for metabolic control and how disrupted clock function may compromise this control in obesity presents clear implication to human health and welfare. As such, research findings will impact greatly on the HEALTH CARE COMMUNITY. We will disseminate findings by publishing primary papers and reviews in high impact journals, and presenting work at national and international meetings. We anticipate that the proposed work will produce 2-4 high-quality primary research papers.

Our findings will be of interest to the GENERAL PUBLIC due to the prevalence of obesity and 24hr lifestyles in our modern society. At its most basic, the work will engage sections of the populous who wish to learn about their health and human physiology. This work also has realistic potential to inform the general public about how dietary habits (what you eat and when you eat it) are dictated by the brain and how disruption of normal circadian rhythmicity can adversely affect health. Research findings will be delivered to the general public through public engagement activities (e.g. brain awareness week), as well as through mass media. For example, our recent article in Science was reported widely in national and international newspapers, on local radio, and on the intranet.

The proposed research is of interest to PHARMACEUTICAL COMPANIES due to direct implications for human metabolic disease. Pharmaceutical industry investment into circadian biology is rapidly growing due to the fact that circadian dysfunction has been linked to sleep disorders, mental health disorders, cancer, inflammation, and aging. In the context of "building partnerships to enhance take-up and impact, thereby contributing to the economic competitiveness of the United Kingdom", our laboratories are currently involved in collaborations with Pfizer and GSK on circadian-related projects, and regular communication with these companies will ensure research findings are taken-up by and impact upon industrial beneficiaries. The Faculty of Life Science at Manchester has taken a strong proactive role in developing links with major pharmaceutical companies, enhancing public communication of science, as well as identification and development of commercialisation opportunities. There are dedicated members of staff employed within the Faculty to assist in these areas.

Benefits of this research to the UK ECONOMY are neither immediate nor guaranteed. However, metabolic disorders (eating disorders, obesity, cardiovascular disease, diabetes etc) are, and will continue to be, a massive burden on the national health care service. This will only increase with the aging population, in which circadian and metabolic disturbance is common. Thus, future economic benefits may be substantial.

This proposal also offers a unique and significant opportunity for high level in vivo training of the research associate , and any PhD students joining for related work. This is a significant benefit as a lack of in vivo research training has been highlighted as a weakness in UK bioscience.