Following the excellent settlement for the overall Research Base announced at the Comprehensive Spending Review, we are all now busy setting down the next draft of our so-called Delivery Plan, so this week’s blog will be comparatively short. One day last week involved a meeting with George Freeman, MP for mid-Norfolk and Chair of the All-Party Parliamentary Group on Science and Technology in Agriculture, as well as a reception (with all the Research Councils) for members of the new Parliament with an interest in Science and Technology, hosted by the Parliamentary Office of Science and Technology.
Biologics are a significant part of our portfolio, and I attended a reception hosted by UCB who focus on their development in both the UK and Belgium.
I gave an academic science talk at the Metabolic Research Laboratories at the University of Cambridge, where my host, Toni Vidal-Puig, introduced me to the concept of allostasis. Allostasis is to be contrasted with the more familiar homeostasis, which describes the concept that (living) systems seek to maintain certain system variables (e.g. the blood glucose concentration) at particular levels (and exploit sophisticated control systems in doing so). Allostasis is in some senses a broader concept, as it describes the concept of maintaining stability through change, and thereby incorporates the systems that maintain the homeostatic set point (or points). Allostatic load then describes the level of demand on systems for correction, and is seen as the normal physiological demands. By contrast, allostatic overload describes a state of prolonged demand that will ultimately cause the system to fail if not corrected. Vidal-Puig and his and colleagues have applied the concept of allostatic overload with success to the aetiology of metabolic syndrome.
As is well known, the metabolic syndrome, obesity and diabetes are increasing at enormous rates in ‘developed’ countries, albeit that they are not inevitably coupled (lean people, and mice, can become diabetic, while some obese persons, and mice, do not). The ‘big idea’ is that it is not obesity per se that leads to metabolic syndrome and diabetes but increasing obesity eventually causes an overload on the body’s ability to store fat in the right places, i.e. adipose tissue, such that lipids of various kinds start appearing elsewhere, causing lipotoxicity and it is this lipotoxicity that leads to the sequelae of metabolic syndrome and diabetes. This would then imply that it is a derangement of lipid, rather than glucose, metabolism that is the main cause (as opposed to effect) of (at least type 2) diabetes. Certainly there is now much evidence for this lipotoxicity story, summarised in a recent special issue of BBA. A particularly striking piece of evidence in favour of this view of diabetes occurring by fat production exceeding the possible adiposity (in adipose tissue) of an organism comes from the ob/ob mouse that lacks leptin is both very obese and prone to diabetes. If a further mutation is made that causes the overexpression of adponectin in the ob/ob mouse, the mass of adipose tissue increases but the control of carbohydrate metabolism is improved.
Protein- (e.g. kinase-)mediated cellular signalling and small molecule metabolism are usually studied in different labs, and thus a great chance of integrating them is missed. My attention was also drawn to a very nice review by Sethi and Vidal-Puig that is starting to remedy this.
I tend to be a fan of ‘big ideas’ that incorporate general principles that seem to be true, and like hormesis, on which I blogged before, allostasis seems to be an important concept with considerable explanatory (and predictive) power, and one offering unexpected and novel therapeutic targets. Sometimes, as apparently in economics, the most important things that need intervention may be quite distant from those commonly believed to be causal.
The announcement of an important genome of interest to BBSRC having been sequenced is almost a weekly event, and this week’s announcement of the sequencing of the rubber tree genome by a team including TGAC is an important milestone for a classical organism of land-based industrial biotechnology. This changes the game for advanced breeding techniques to improve productivity and other traits, and – given that a significant part of the funding came from Malaysia – is an excellent example of BBSRC leveraging external funding to develop the Knowledge-Based BioEconomy.
- Kim, J.Y.et mult. al. (2007) Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117, 2621-2637. Full free text
- McGarry, J.D. (2002) Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51, 7-18
- Sethi, J. K. & Vidal-Puig, A. (2010). Wnt signalling and the control of cellular metabolism. Biochem J 427, 1-17
- Vidal-Puig, A. & Unger, R.H. (2010) Special issue on lipotoxicity. Biochim Biophys Acta 1801, 207-8
- Virtue, S. & Vidal-Puig, A. (2008) It‘s not how fat you are, it’s what you do with it that counts. PLoS Biol 6, e238. Full free text
- Virtue, S. & Vidal-Puig, A. (2010) Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome: an allostatic perspective. Biochim Biophys Acta 1801, 338-49