Andrea Haqq is a Pediatric Endocrinologist at the Stollery Children’s Hospital, Professor of Pediatrics and Adjunct Professor of Agricultural, Food and Nutritional Sciences at the University of Alberta. Dr. Haqq completed her MD at the University of Calgary and pediatric residencies at BC Children’s Hospital and the Children’s Hospital of Eastern Ontario. Following a pediatric endocrinology fellowship at Oregon Health and Science University, Dr. Haqq held a clinical and academic position at Duke University. She re-located to Edmonton in July 2009. Dr. Haqq has a strong clinical and research interest in hormonal regulation of food intake, particularly in childhood obesity and Prader-Willi Syndrome (PWS).
Pathogenesis of Prader-Willi Syndrome
The preponderance of my research has focused on understanding the pathogenesis and therapy of Prader-Willi syndrome (PWS), a genetic syndrome characterized by hyperphagia, excess weight gain and sexual immaturity. Through early investigations we elucidated the neuroendocrine profile of PWS and determined that while plasma ghrelin (a hunger-inducing hormone) levels are suppressed in adults and children with non-genetic obesity, ghrelin levels are markedly increased in body mass index (BMI)-matched children with PWS. This finding suggests that PWS serves as a unique model of ghrelin excess, which may explain the ravenous appetite and progressive weight gain that characterize the condition. My group also conducted one of the first controlled clinical trials of the use of growth hormone (GH) in Prader-Willi syndrome, providing key data allowing for FDA approval for the use of GH in PWS in the United States. Our studies demonstrated that GH reduces adipose tissue, increases lean body mass, increases REE and showed a trend toward improving pulmonary function and sleep quality I have also expanded the understanding of the role of the leptin-melanocortin signaling pathway and brain-derived neurotrophic factor haploinsufficiency in PWS. We have completed metabolic profiling of a cohort of PWS children compared to obese controls. Key findings show that PWS females, but not males, had hyperghrelinemia, hyperadiponectinemia, hypoinsulinemia, and decreased glycine and tyrosine and BCAA. Collectively, these studies enhance the understanding of the hormonal control of appetite and energy balance and have important, broad implications for understanding general childhood obesity and weight control.
In the previous gut microbiota study, our group found a link between the unrelenting feeling of hunger and the altered gut bacteria composition in children with Prader–Willi syndrome (PWS). Gut dysbiosis may be a target for appetite and weight control in PWS. Dietary fibers are well known for their satiating effects and metabolic benefits in humans, which are mediated partly by modulating the gut microbiota. Our group is conducting a fiber intervention study to determine if prebiotic fibers can support the growth of good bacteria and help them thrive in the gut of kids who have PWS, and if this can help reduce their excessive appetite and weight gain. We will apply both targeted and untargeted metabolomics analyses that will allow us to profile as many metabolites as feasible to maximally cover metabolic processes and pathways. We may be able to identify metabolomics patterns associated with improved hyperphagic symptoms and metabolic outcomes and offer some new insights into the complex biological processes regulating appetite and body weight in individuals with PWS.
The "Healthy Obese"
I am interested in understanding why some children and adolescents with obesity are protected from developing metabolic co-morbidities, such as insulin resistance and cardiovascular disease. PWS provides a model that may help to explain this phenomenon of the patient with “healthy obesity”. Studies from my laboratory have demonstrated that PWS is associated with relative hypoinsulemia and hypersensitivity to insulin action, associated with hyperadiponectinemia, low levels of interleukin 6 and C-reactive protein, and relatively low visceral fat deposition. The preservation of insulin sensitivity might be explained by the differential patterns of fat distribution or differences in autonomic function between PWS and other subjects with non-syndromic obesity. In collaboration with Dr. Chris Newgard (Duke University), I have helped elucidate detailed metabolic profiling (hormones, cytokines, metabolites, and physiologic variables) of obese and lean individuals. We identified a unique branched-chain amino acid (BCAA)-related metabolite signature in individuals with obesity that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. In an ongoing study in collaboration with Dr. Carla Prado (University of Alberta), we are testing the metabolic load-capacity model in children with non-syndromic obesity. This model has been proposed to explain the relative contribution of adiposity and muscularity to physiological function in adults. Preliminary data analysis revealed that children with ‘metabolically unhealthy obesity’ had greater load-capacity index than those with ‘metabolically healthy obesity’. Using ultrasound measures, we also found that muscle echo intensity was positively associated with insulin resistance. As higher muscle echo intensity suggests fatty infiltration in muscles, our preliminary findings indicate that presence of ectopic fat also helps to distinguish ‘healthy’ from ‘unhealthy obesity’ phenotypes. Ongoing studies may shed new light on the pathogenesis of insulin resistance and life-threatening metabolic complications of obesity.
Development of Anti-Obesity Agents
Our research team was also one of the first to explore novel means of modulating ghrelin levels in PWS by pharmacologic agents. Our group showed that subcutaneous administration of octreotide over 5-7 days duration produced a 67% reduction in ghrelin levels in four children with PWS. These results were confirmed by others. The short-term reduction of fasting ghrelin concentrations did not alter food intake, body weight, body composition, resting energy expenditure or growth hormone markers. Our recently published results of a new ghrelin-O-acyltransferase (GOAT) inhibitor, shows safety and tolerability of this medication in PWS. Our group continues to explore novel anti-obesity agents (e.g.setmelanotide, carbetocin) in collaboration with industry sponsors (Rhythm Pharmaceuticals and Levo Therapeutics, respectively). Results of the effects of setmelanotide for treatment of obesity and hyperphagia in Bardet-Biedl syndrome are submitted for publication and results on carbetocin for the treatment of hyperphagia and obesity in PWS are being analyzed for publication.