FONDATION-IPSEN

As we become more sedentary and better fed, the human race is faced with an epidemic of obesity and diseases such as type II diabetes. Although the correlation between body weight, food intake and exercise seems obvious, the regulatory mechanisms that link exercise, muscle biology, hormones and metabolism are not well understood. The focus of this year’s colloquium on Endocrinology hosted by the Fondation IPSEN is to gain an overview of the complexity of these pathways, to discuss the processes common to the various body systems involved and to identify possible therapeutic targets. Twelve international speakers will present their latest research at the meeting, which has been organised by Bruce Spiegelman (Dana Faber Cancer Institute and Harvard Medical School, Boston, USA) and the Fondation IPSEN (Paris, France). It will be held in Paris on December 5, 2016.

The most obvious effects of exercise are on skeletal muscles, increasing muscle volume, strength and contractility. More importantly, exercise both maintains and increases the insulin sensitivity of muscle and affects the metabolism of the whole body by stimulating the uptake of glucose by muscles (Anna Krook , Karolinska Institutet, Stockholm, Sweden ). A decrease in muscle insulin sensitivity is a big contributor to the onset of type II diabetes. The effectiveness of exercise regimes is modified by the availability of nutrients: the composition of the diet and the timing of meals in relation to exercise both alter the blood-borne signals that ultimately influence fuel metabolism and utilization (John Hawley , Mary Mackillop Institute for Health Research, Melbourne, Australia ). Among these signals are the recently discovered hormones released by contracting muscles, now called myokines, such as the soluble peptide irisin. The role of steroid hormones in improving cardio-vascular fitness in response to exercise is being tested in population studies (Claude Bouchard , Pennington Biomedical Research Centre, Louisiana, USA ).

Metabolic stresses, such as low oxygen, ischaemia or glucose deprivation, stimulate the regulatory molecule AMP kinase, which acts as a cellular fuel gauge, providing an essential link between exercise, insulin signaling and the regulation of energy supplies. As well as its essential role in skeletal muscle, this molecule is pivotal in balancing the supply of nutrients to cells with the demand for energy throughout the body (Benoit Viollet , Institut Cochin-U1016 INSERM, Paris, France ). Small RNA molecules known as micro-RNAs, which modulate the translation of DNA into proteins through their effect on messenger RNAs, also play a role in both skeletal muscle differentiation and in type II diabetes in response to exercise (Krook ).

Ultimately, energy production depends on the series of enzymatic reactions known as the citric acid cycle, which takes place in the mitochondria, the cell’s power generators. When the demand for energy goes up as a result of exercise, one pathway that coordinates the increase in size and number of mitochondria and optimizes the utilization of fuel requires the activation of the transcription factor EB (TFEB) (Marco Sandri , University of Padova, Padova, Italy ).

Muscles atrophy as a result of disuse, ageing and cachexia, the wasting experienced in terminal cancer. In rat muscles, the expression of genes involved in mitochondrial energy metabolism changes with ageing. The functional loss of muscle innervation seen in both ageing and cachexia is reflected in changes in genes responsible for the integrity of the neuro-muscular junction (David Glass , Novartis Institute for Biomedical Research, Cambridge, USA ). In atrophying muscle, a set of genes is activated that produce muscle-specific enzymes responsible for labelling proteins for degradation in special organelles termed proteasomes (Alfred Goldberg , Harvard Medical School, Boston USA ). Environmental stress activates compensatory mechanisms important for the maintenance of cell functions and their failure is a cause of cellular ageing, for example, the reduction in mitochondrial health that accompanies muscle atrophy. However, some of these effects can be ameliorated by exercise (Sandri ).

A pivotal molecule in mediating responses to external stimuli is PGC-1α, which regulates both the transcription of the genes involved in metabolism and the regulation of mitochondrial biogenesis. Increased activity of PGC-1α improves endurance, reduces fibre damage and muscle atrophy, and is important in determining muscle fibre type. PGC-1α may lie at the heart of improving the regenerative capacity of muscle through training: it activates both macrophages, which remove damaged muscle fibres, and the satellite cells that generate replacement fibres (Christoph Handschin , University of Basel, Basel, Switzerland ).

PGC-1 α is also important in another tissue central to energy regulation, the type of fat known as brown adipose tissue (BAT). This converts chemical energy into heat in a process known as thermogenesis, part of the body’s adaptive response to cold. Its presence in humans has been controversial but BAT is now recognized to form deposits deep in the neck and is found in some subcutaneous fatty tissue. It is distinct from white adipose tissue, the main form of fat deposited in the human body but it has recently been discovered that white fat can be converted to BAT through an intermediate ‘beige’ form (Francesco Celli , Virginia Commonwealth University, Richmond, USA ). The hormonal signals that stimulate the conversion and the activation of beige and brown fats in response to cold, and how this increases the breakdown of post-prandial glucose, are being studied. The pathways through which these hormonal signals activate PGC1α and a second molecule found in BAT, termed UCP-1 (or thermogenin) may link exercise and thermogenesis: the hormone irisin produced by active skeletal muscle has been implicated stimulating the conversion of white to brown fat (Spiegelman ).

As well as its effects on muscle and fat body, exercise works in less obvious ways to keep the brain healthy. Problems with the breakdown of kynurenine, produced from the amino acid tryptophan and a precursor of enzymes involved in fat and carbohydrate metabolism, are implicated in several neuroinflammatory and psychiatric diseases, including stress and depression (Jorge Ruas , Karolinska Institutet, Stockholm, Sweden ). During exercise, kynurenine is detoxified in skeletal muscle by conversion to kynurenic acid, which cannot cross the blood-brain barrier. This is yet another pathway involving PGC1α, a further example of the complexity of exercise-linked regulatory mechanisms. Yet another effect of exercise, at least in adult mouse brains, is to increase the birth of new neurons in the hippocampus, which helps to support learning and cognitive function. Irisin has a role here too: it increased the expression of the gene coding for the growth factor BDNF, essential for hippocampal neurogenesis (Christiane Wrann , Dana Faber Cancer Institute, Boston, USA ).

The research to be presented at the meeting will emphasise not only how important exercise is for maintaining a healthy metabolism but also the multiple ways in which it has its effects. Many of the results that will be discussed also provide leads for the development of therapeutics for use when exercise alone fails to have the desired effect or is inappropriate.

Jennifer Altman

27^th November 2016

The Fondation IPSEN

Established in 1983 under the aegis of the Fondation de France, the ambition of the Fondation IPSEN is to initiate a reflection about the major scientific issues of the forthcoming years. The long-standing mission of the Fondation IPSEN is to contribute to the development and dissemination of scientific knowledge by fostering interaction between scientists and clinicians. It has developed an important international network of scientific experts who meet regularly at meetings known as Colloques Médecine et Recherche , dedicated to three main topics: neurosciences, endocrinology and cancer science. Moreover the Fondation IPSEN has started several series of meetings in partnership with the Salk Institute, the Karolinska Institute as well as with the science journals Cell and Science . The Fondation IPSEN produced several hundred publications and more than 250 scientists have been awarded prizes and grants.

www.fondation-ipsen.org

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