Andrew Murray, University of Cambridge, UK

Paul Meakin, University of Leeds, UK

https://doi.org/10.36866/pn.116.40

We are a few months into our roles as co-Leads of one of the Society’s newest Themes, and though the decision to separate Metabolism from Endocrinology was not our own we both welcome this development. The opportunity to fly the flag for Metabolic Physiology comes at an exciting time, with technical advances in metabolic research arriving in the nick of time as we tackle problems that include some of the gravest health issues facing society.

For ordinary people living in the developed world it has, it seems, never been easier nor cheaper to acquire food packed with calories yet containing little else of nutritional value. Equally, it has become easier to avoid using those calories by adopting increasingly sedentary lifestyles and spending our days staring at screens in our homes and offices. The consequences of this behavioural shift have arrived in various forms – obesity, diabetes, cardiovascular disease, fatty liver disease – all well documented to be on the rise but still incompletely understood, and with life spans increasing, each a significant and growing burden for our society and health services.

The scope of metabolic physiology reaches beyond the realm of metabolic diseases, however, arguably touching upon all other areas of physiology. As such, this is a diverse and dynamic area of physiology, combining fundamental research with a broad range of applications to health and disease. A taste of this came recently when, in one of our first tasks as Theme Leads, we found ourselves reviewing abstracts for Physiology 2019. Of the 408 abstracts submitted, 94 were submitted under the Metabolism & Endocrinology Theme. This was the most for any Theme, and perhaps explains the rationale for separating the two areas in future. Alongside research investigating the consequences of malnutrition in various forms and the aetiology of diabetes and fatty liver disease, were abstracts submitted for symposia on the circadian regulation of metabolism, the roles of free radicals in skeletal muscle function, and the physiology of brown adipose tissue (BAT). We also came across studies investigating metabolic regulation in contexts as diverse as excitation-contraction coupling in muscle, cell-cell tethering in renal tubule epithelia, and placental function in hypoxia. In the latter case, this reflects one of two trends in metabolic research that bookend the life-course. On one hand, there is growing interest in the metabolic aspects of fetal development and in how the intrauterine environment shapes metabolic function in the offspring with consequences for lifelong health. At the other end of the lifespan we find great interest in the role of mitochondrial function in the ageing process, and in the lifestyle factors that might permit or prevent a healthy ageing phenotype.

Metabolic physiology is therefore naturally interdisciplinary, and the links with endocrinology are particularly profound. Despite the separation of these two Themes, we will continue to work closely with the Endocrinology Theme Leads particularly at a time when the boundaries between the two areas are becoming a little more blurred. The hormonal control of tissue metabolism and appetite regulation, for example, are well established and understanding these mechanisms has been essential to our comprehension of how metabolic function is integrated at a whole-body level and what happens when it goes wrong. Of more recent interest, however, are the signalling roles now known to be played by many small molecule metabolites. There are, for instance, a number of G-protein coupled receptors known to be activated by metabolites including various fatty acids, lactate and ketones, which in turn, regulate aspects of metabolic function, e.g. by potentiating insulin secretion at pancreatic alpha cells or suppressing lipolysis in adipocytes. Similarly, a number of nuclear hormone receptors are also activated by metabolic ligands. Perhaps the best known example being the PPAR family of transcription factors which are expressed in a tissue-specific manner, and which alter the expression of genes involved in fat metabolism to match tissue metabolism to substrate supply when activated by fatty acids or their derivatives.

There is therefore a growing recognition that many metabolites, previously considered mere substrates in pathways or building blocks for various macromolecules, are themselves cellular mediators of metabolic function and/or distinct plasma-borne signatures of physiological and pathophysiological states. The term oncometabolite was initially coined in reference to R-2-hydroxyglutarate (Ward et al., 2010), and later extended to encompass succinate, fumarate, lactate and S-2-hydroxyglutarate. These intermediates accumulate in cancer cells downstream of mutations to genes encoding metabolic enzymes, and have been shown to aid tumorigenesis through various oncogenic signalling cascades that result in immunosuppression and epigenetic remodelling. More recently, oncometabolites have been found to accumulate in non-cancerous tissues under pathological conditions, influencing cardiac metabolism and contractile function (Karlstaedt et al., 2016), and with succinate in particular proposed to play a role in ischaemia/reperfusion injury by mediating mitochondrial reactive oxygen species (ROS) generation (Chouchani et al., 2014). Meanwhile, the term immunometabolite has been proposed for small molecules which act as signatures of immune cell activation including succinate, itaconate, serine and S-2-hydroxyglutarate (de Goede et al., 2019), the latter of which alters DNA methylation to play a role in 
T-cell differentiation and proliferation (Tyrakis et al., 2016).

The discovery of active BAT deposits in adult humans, reported in several articles published in 2009, catalysed a wave of studies that aimed to understand its functional significance, particularly regarding body weight regulation (Betz et al., 2015). As a fat-burning form of adipose tissue, BAT naturally represents an attractive target for the treatment of obesity and its comorbidities, and a great deal of research has since sought to understand the mechanisms regulating BAT thermogenesis and uncover any factors that promote the expansion of BAT deposits. A number of peptide mediators of BAT development and function have been uncovered, including for example the hormone irisin. Notably, a handful of small molecule mediators of the browning process have been described, including inorganic nitrate and â-aminoisobutyric acid (BAIBA), which is secreted by myocytes and rises in human plasma in response to exercise training. BAIBA was shown to increase the expression of BAT-specific genes in the white adipose tissue of mice, enhancing metabolic rate and improving whole-body insulin sensitivity (Roberts et al., 2014).

The discovery of novel metabolic mediators of physiological function has been aided by the development of high-throughput technologies, initially developed as tools for analytical chemistry and subsequently applied to the metabolic profiling of tissues and biofluids (Griffin et al., 2011). Alongside the development of data analysis software, and aided by data sharing platforms, techniques such as NMR spectroscopy and mass spectrometry have greatly expanded our capacity to comprehend global metabolic disturbances. Collectively termed metabolomics, these techniques can be applied in a targeted manner to fully profile adjustments to intermediates across a metabolic pathway or a collection of related pathways, or in an unbiased manner to aid biomarker discovery and provide fodder for hypothesis generation. Advances in lipid-profiling are revealing distinct patterns of change across the many classes and species of lipid, and shedding new light on the possible functional properties of a hitherto overlooked class of metabolites, whilst the novel application of mass spectrometry imaging is highlighting the importance of their distribution across tissues (Hall et al., 2017).

This quantum leap in our capacity to understand the full metabolic state-of-play in our model systems is perhaps the metabolic equivalent of the Human Genome Project. The challenge for metabolic researchers contemplating such a rich resource of data will be to extract the signal from the noise and to determine the physiological significance of these findings. Metabolic physiology is in flux; there are challenges ahead but it is an exciting time to come along for the ride.

References

Betz MJ, Enerback S (2015). Human brown adipose tissue: what we have learned so far. Diabetes 64(7), 2352–2360.

Chouchani ET et al. (2014). Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515(7527), 431–435.

de Goede KE et al. (2019). Let’s enter the wonderful world of immunometabolites. Trends Endocrinol Metab 30(6), 329–431.

Griffin JL et al. (2011). Metabolomics as a tool for cardiac research. Nat Rev Cardiol 8(11), 630–643.

Hall Z et al. (2017). Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology 65(4), 1165–1180.

Karlstaedt A et al. (2016). Oncometabolite d-2-hydroxyglutarate impairs alpha-ketoglutarate dehydrogenase and contractile function in rodent heart. Proc Natl Acad Sci USA 113(37), 10436–10441.

Roberts LD et al. (2014). beta-Aminoisobutyric acid induces browning of white fat and hepatic beta-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 19(1), 96–108.

Tyrakis PA et al. (2016). S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate. Nature 540(7632), 236–241.

Ward PS et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17(3), 225–234.