Endocrine Abstracts

Introduction: Obesity is one of the biggest health challenges we currently face. Obesity results from imbalance of energy consumption and expenditure. Genetic studies on monogenic forms of obesity and Genome Wide Association studies have revealed neuronal mechanisms of genesis of obesity and/or leanness. We report a novel disorder of increased energy expenditure with severe failure to gain weight and increased brown fat.

Case report: The proband is a white Caucasian 3-year-old female, who currently weights only 2.7 kg. Despite receiving a high calorie intake of 180–200 kcal/kg/day she has failed to gain weight. All the investigations for failure to thrive are negative. Biochemically she has hypoglycaemia, continuous fatty acid oxidation, undetectable IGF-1 and IGFBP-3, secondary hypothyroidism and increased resting energy expenditure as repeatedly measured by indirect calorimetry. This increased energy expenditure is associated with depletion of fat from adipose tissue and the appearance of increased brown fat as demonstrated by immunohistochemistry.

Discussion: So far no human disorder has been described with this constellation of clinical features. This patient’s biochemical investigations suggest that rather than storing fat and carbohydrates this patient is continuously burning these fuels simultaneously. There are several different rodent models of increased energy expenditure associated with depleted triglycerides in adipose tissue with increased fat oxidation (due either to loss of function or gain of function of the following genes ACC2, SIRT1, SRC2/3, Foxc2, PTP1B, DGAT, Eif4BC, NFAT). Recently several new genes have been identified which control brown fat formation (such as PRDM16 and BMP7). Using a candidate gene approach we have sequenced the ACC2, RIP140 and FTO genes and found no genetic defects. Along with metabolic studies to indentify the abnormalities of metabolic pathways whole genome exome sequencing is being performed to identify the underlying genetic basis. Understanding the mechanisms of the increased energy expenditure will provide new knowledge about energy expenditure and will have important potential implications for treating common forms of obesity.