Lausanne, Switzerland, July 17, 2014 – New research led by scientists at the Nestlé Institute of Health Sciences (NIHS) could provide a clue to combat the growing epidemic of metabolic disorders. This work makes an important contribution to the knowledge and expertise that NIHS can apply in the future to develop nutritional solutions for improving metabolic health.
AMP-activated protein kinase (AMPK) is an enzyme that acts as a central molecular switch whose activation has many beneficial effects on metabolism. AMPK can be naturally activated by exercise in muscle, but if we also knew how to activate AMPK, for example, by diet, we could better control energy balance and maintain metabolic health. Regulation of AMPK is complex: it is controlled by the interplay between 3 subunits (a catalytic α subunit and regulatory β and γ subunits) and each subunit has multiple isoforms. A handful of synthetic small molecules have been reported to directly stimulate AMPK but, apart from thienopyridones (which stimulates AMPK through binding to one of the β subunit isoforms), precisely how they work has not yet been described.
Through a highly successful collaborative effort by an international team of scientists led by Prof. Kei Sakamoto and his group at NIHS, a research project was undertaken to characterise a recently identified AMPK activator. They identified a unique mechanism of action that displays a preference for a particular AMPK α-complex isoform.
These findings provide new insights into targeting AMPK more selectively by small molecules. The full research report is available in the latest issue of Chemistry & Biology. Kei’s team also recently reported a means to boost AMPK activity by combinations of small molecules (Ducommun et al., 2014; Reference 2).
‘Our research shows it’s possible to develop α isoform-specific activators for use alongside β-selective activators’, Kei concludes. ‘This is an important step towards a more complete understanding of the mechanism by which small molecules activate AMPK, and will help contribute to the design of more selective AMPK activators that could be used to maintain energy balance.’
This work is aligned with the mission of NIHS, which is to better define and maintain health through targeted nutrition. Studying AMPK is one avenue that NIHS is exploring to better understand metabolic homeostasis in relation to obesity and diabetes, and whether this can be modulated through diet and nutrition.
For enquiries, please contact:
Laura Camurri, Communications, NIHS
1) Hunter RW, Foretz M, Bultot L, Fullerton MD, Deak M, Ross FA, Hawley SA, Shpiro N, Viollet B, Barron D, Kemp BE, Steinberg GR, Hardie DG, Sakamoto K. Mechanism of action of Compound-13: an α1-selective small molecule activator of AMPK, Chemistry & biology. Vol 21, Issue 7, 17 July 2014; 866-879.
2) Ducommun S, Ford RJ, Bultot L, Deak M, Bertrand L, Kemp BE, Steinberg GR, Sakamoto K. Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662, Am J Physiol Endocrinol Metab. 2014 Mar; 306(6):E688-96.