The study of physiology at the extremes provides a unique opportunity to not only improve fundamental understanding of basic physiological principles but also permits the advancement of knowledge in relation to rare, underserved and/or fascinating populations. Individuals with achondroplasia, the most common form of disproportionate short stature, are reported to be at greater risk of early mortality compared to average-height individuals, and yet the causes remain unknown. Furthermore, research into the metabolic basis of this condition and its associated co-morbidities has not yet extended beyond several cross-sectional analyses of fasted cardiometabolic blood markers and resting metabolic requirements. Given the high prevalence of obesity amongst individuals with skeletal dysplasia, at least when classified using body mass index, it is remarkable that no previous research has attempted to examine which components and regulators of energy balance may be responsible for this predisposition towards obesity and so may represent logical targets for health promotion (e.g., medicines to modify underlying metabolism and/or lifestyle interventions to modify behaviours). To this end, this thesis represents the first research to study individuals with extreme morphologies, both to provide specific insight into the metabolic health of individuals with achondroplasia but also to provide wider context using extremely large and small individuals as comparator groups – thus informing whether any observed physiological differences are primarily attributable to the gene substitution that causes achondroplasia, or to an effect of body size per se. This thesis begins with an initial exploratory analysis of protocols and methods to measure components of energy balance, before applying those approaches to individuals with extreme morphology. That specific focus on achondroplasia revealed numerous interesting and impactful findings. Firstly, whilst the typical levels of adiposity seen in achondroplasia cannot be readily compared with average-height controls or measured against set thresholds for chronic disease risk, the overall picture from the present data collection supports the view that individuals with achondroplasia are somewhat predisposed to accumulating excess body fat. Therefore, a reduction in adiposity would generally be advisable and improve various aspects of health and quality of life. In terms of underlying metabolism, individuals with achondroplasia exhibited a relatively high resting metabolic rate and an increased propensity to oxidise carbohydrate (especially ingested sugar), whereas a number of circulating metabolites that are generally indicative of cardiometabolic disease risk (e.g., plasma glucose and blood lipid profile) were lower than might be expected for individuals with excess adiposity (although there was some evidence of insulin resistance within adipose tissue). Hormonal profiles that regulate metabolism and energy balance were generally within typical ranges and so (other than a slight tendency towards elevated hunger hormones) inherent metabolic differences could not specifically explain these individuals’ predisposition towards obesity. However, analysis of behavioural components of energy balance indicated that, whilst individuals with achondroplasia do not necessarily eat inappropriately for their size (and therefore basal energy requirements), their objectively measured physical activity levels were low (particularly in terms of engagement in regular moderate-vigorous intensity movement – i.e., exercise). Therefore, accepting that adaptations to specific exercise modalities may be required, it is logical to conclude that individuals with achondroplasia would benefit from adherence to standard physical activity recommendations - both in terms of increased total energy expenditure potentially encouraging a more negative energy balance (and thus weight-loss), and in terms of the direct benefits of exercise independent of energy balance and weight-loss (i.e., improved cardiorespiratory fitness, mental health, mobility and quality of life). It is hoped that this thesis has opened a gateway for further research in this area, not only to improve the lives of those living with restricted growth conditions, but to continue learning from the extremes of physiology, irrespective of the rarity of the disorder (O’Rahilly, 2021).
Human Morphology, Energy Balance and Metabolic Health: (Alternative Format Thesis)
Merrell, L. (Author). 25 Mar 2026
Student thesis: Doctoral Thesis › PhD