TMCnet News

The 14th Colloque Médecine et Recherche of the Fondation Ipsen in the Endocrinology series: "A time for metabolism and hormones"
[December 04, 2014]

The 14th Colloque Médecine et Recherche of the Fondation Ipsen in the Endocrinology series: "A time for metabolism and hormones"


The challenges posed by modern lifestyles - artificial light, shift work and jet lag among others - are testimony to the robustness and plasticity of circadian regulation, and reflects the centrality of body clocks in the maintenance of health. Unravelling the complex mechanisms of circadian rhythms is revealing how disruptions of this coordination contribute to disease and pointing to new treatments for conditions as varied as obesity and sleep disorders.

Many biological activities fluctuate in a roughly 24-hour cycle: sleep-wake and feeding are two obvious ones but mood, cognition, circulation, cardiac function, digestion, immune responses and the release of some hormones are all regulated by a hierarchy of clock mechanisms in the body. Although much is now known about the networks of genes and proteins that form these clocks, new research is revealing just how intricate this machinery is and how important internal clocks are for health and disease. At the 2014 Colloque Médecine et Recherche in the Endocrinology series hosted by Fondation IPSEN, 13 leading scientists from Europe and the USA will focus on recent developments in understanding how clocks regulate the body's energy supply, with implications for treating obesity, type 2 diabetes and even cancer. The meeting is organised by Paolo Sassone-Corsi (University of California, Irvine, USA) and Yves Christen (Fondation IPSEN, Paris, France).

Most organisms, from bacteria to humans, display daily cycles of activity that are linked to external conditions. The most obvious in animals are being asleep or awake, and feeding or resting. Known as circadian rhythms because they have a period of about a day, they persist under experimentally constant conditions, which indicates that they are driven by an internal clock or circadian oscillator. Normally, exposure to daily fluctuations in external conditions, such as the cycle of light and dark entrains the circadian oscillators to the environment. It is now well established that circadian clocks exist at many levels in the body, in single cells, in tissues, organs and systems, governing the activity of many biochemical and physiological processes, including digestion, metabolism and hormone secretion (Joseph Bass, Northwestern University, Chicago, USA). Even tumour cells have their own clocks, although they also respond to the host's clock (Steven Brown, University of Zurich, Switzerland).

These multiple clocks form a network of oscillators that is essential for coordinating the body's activities. The oscillations provide a dynamic equilibrium that prevents cellular processes from becoming desensitized (Stafford Lightman, University of Bristol, UK) and provides plasticity to cope with changes in external conditions, such as availability of food (Sassone-Corsi).

The oscillations arise within cells through the periodic activation and silencing of a number of core clock genes, involving complex molecular feedback and feed-frward loops operating at several levels (Joseph Takahashi, University of Texas Southwestern Medical Center, Dallas, USA; Michael Hastings, MRC Laboratory of Molecular Biology, Cambridge, UK). Two clock proteins, which activate the main clock genes, also interact with the regulatory regions of 1000s of other genes. Specific transcription factors are linked to different phases of the circadian cycle in liver cells (Mitchell Lazar, University of Pennsylvania, Philadelphia, USA). Epigenetic mechanisms such as chromatin remodeling operate in parallel to increase the plasticity of the response (Sassone-Corsi), and the stability of messenger MRA, which affects its translation into proteins, is controlled by a cyclically expressed gene (Carla Green, University of Texas Southwestern Medical Center, Dallas, USA). At yet another level, chemical modification of the activity of some proteins by a process known as phosphorylation is under circadian control (Louis Ptácek, Howard Hughes (News - Alert) Medical Institute, San Francisco, USA). Oscillations in oxidation and reduction reactions may also make a substantial contribution, an ancient mechanism found in almost all organisms (Akhilesh Reddy, University of Cambridge, UK).



Food seems to be the factor that entrains the cellular clocks regulating metabolic activity. The fruit fly, Drosophila melanogaster, has two opposing clocks involved in the rhythm of feeding: one, in the fat body (the fly's liver), promotes nutrient storage; the other, in the nervous system, regulates release of nutrients. Altering the time when food is available affects the fat body clock but not the neural clock (Amita Sehgal, University of Pennsylvania, Philadelphia, USA). The importance of cellular clocks in metabolic control is demonstrated by disrupting circadian genes in mice, which develop symptoms of metabolic syndrome such as weight gain and dysfunctional glucose regulation (Bass). Conversely, mice lacking the gene for Nocturnin, a rhythmically produced enzyme involved in mRNA stability in metabolically active tissues, are resistant to weight gain through their inefficient processing of dietary lipids (Green). A transcription factor, Rev-erb, which interacts with the clock genes, is key to circadian regulation of lipid metabolism in liver cells (Lazar) and an enzyme that is a sensor for glucose promotes transcription of the clock genes in a periodic fashion (Ptácek).

The circadian control of metabolism throughout the body seems to be mediated by mitochondria, the power plants in every cell, but metabolism is also independently regulated by sleep and is suppressed by chronic sleep deprivation (Brown). Locomotor activity in Drosophila - the fly's equivalent of the sleep-wake cycle - depends on a multi-oscillator network located in about 150 neurons, with light levels triggering different subsets of neurons involved in morning activity and evening rest (François Rouyer, CNRS UPR 3294, Gif-sur-Yvette, France). Disrupted sleep patterns are common in people on the autistic spectrum and gene mutations disrupting a pathway involving the sleep-regulating chemical melatonin are also linked to autism - mutations affecting clock genes are also possible (Thomas Bourgeron, Institut Pasteur, Paris, France).


The hierarchy of circadian oscillators in cells, tissues and organs requires a coordinator and in mammals this top clock is a small centre in the brain: the suprachiasmatic nucleus (SCN) in the hypothalamus, which coordinates endocrine, metabolic and behavioural rhythms (Hastings). Its 10,000 neurons and glial cells form a tightly coupled pacemaker that receives direct input from the retina, through which it entrains all other oscillators to solar time. The neuronal oscillator in turn depends on the intracellular molecular feedback loops that regulate the clock genes. One pathway directly responsive to the SCN is the hypothalamic-pituitary-adrenal axis, the endocrine pathway mediating circadian variations in the stress response. However, the release of stress hormones also show hourly fluctuations that are independent of SCN input but result from a loop between the pituitary gland and adrenal cortex (Lightman).

About the Fondation Ipsen

Established in 1983 under the aegis of the Fondation de France, the mission of the Fondation Ipsen is to contribute to the development and dissemination of scientific knowledge. The long-standing action of the Fondation Ipsen aims at fostering the interaction between researchers and clinical practitioners, which is indispensable due to the extreme specialization of these professions. The ambition of the Fondation Ipsen is to initiate a reflection about the major scientific issues of the forthcoming years. It has developed an important international network of scientific experts who meet regularly at meetings known as Colloques Médecine et Recherche, dedicated to six main themes: Alzheimer's disease, neurosciences, longevity, endocrinology, the vascular system and cancer science. Moreover the Fondation Ipsen has started since 2007 several meetings in partnership with the Salk Institute, the Karolinska Institutet, the Massachusetts General Hospital, the Days of Molecular Medicine Global Foundation as well as with the science journals Nature, Cell and Science. The Fondation Ipsen produced several hundred publications; more than 250 scientists and biomedical researchers have been awarded prizes and research grants.

You can find other information about Fondation Ipsen on our website: www.fondation-ipsen.org


[ Back To TMCnet.com's Homepage ]