Why are some people fat and others not? OR How would the disease detectives investigate the current obesity epidemic? Robyn McDermott Investigation of an epidemic • Who’s got it and who hasn’t • How are they different? Geography, age, sex, timing, what they ate and drank, what they touched….. • Can we narrow it down to one or two culprits? • Once we have these, what are the mechanisms? • Can we stop the epidemic by removing these? • What if it’s not simple (one bug)? Classic and simple: John Snow, Cholera and the Broad Street Pump The fat story: diabesity in the USA Prevalence of diabetes, Indigenous NQ (WPHC) and Australia (AusDiab), 1999-2000 60 50 40 Non-Indigenous Aboriginal Torres Strait Islander 30 20 10 0 15-24 25-34 35-44 45-54 55-64 Source: McDermott et al, AHR 2003 65+ New and complex: Various theoriesall plausible, all contributing….. 1. Genes, epigenetics, evolution and energy metabolism: the brown fat story 2. Prenatal exposures and “intrauterine programming” 3. New foods: fat, sugar and the microbiome 4. New jobs and leisure: screen time, sitting and sleep deprivation Human migrations and metabolic adaptation to different environmental stressors: a new theory for ethnic obesity variation Source: Sellayah D, et al “On the evolutionary origins of obesity: a new hypothesis. Endocrinology 2014:doi: 10.1210en.2013-2113 Aboriginal adults (Central Australia) 1930s Torres Strait Islanders, 1930’s-40’s Ethnic differences in BAT volume and activation: Caucasians vs South Asians Source: Bakker LEH et al. Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational studyThe Lancet Diabetes & Endocrinology, Volume 2, Issue 3, Pages 210 - 217, March 2014 doi:10.1016/S2213-8587(13)70156-6 Fat ain’t fat The good news: Cold induces brown fat activity and heat production in lean adults, but much less so in obese adults (the bad news) Cold Exposure Thermoneutral Conditions Comparative PET–CT scans reveal the patterns of 18F-FDG uptake in the same subject from the lean group after exposure to cold and under thermoneutral conditions. Source: Lichtenbelt et al. Cold-Activated Brown Adipose Tissue in Healthy Men. N Engl J Med 2009;360:1500-8. Fat ain’t fat: the bad news Lessons from the microbiome project: You are what you eat, and so are the friends that live in your gut. Source: Matthias H Tschöp, Philip Hugenholtz & Christopher L Karp Getting to the core of the gut microbiome Nature Biotechnology 27, 344 - 346 (2009) doi:10.1038/nbt0409-344 Effect of Intestinal Microbial Ecology on the Developing Brain: What goes in… Composition of the gut microbiota in a neonate is affected by numerous external and internal factors, beginning at birth. Source: Martha Douglas-Escobar, MD; Elizabeth Elliott; Josef Neu, MD. Effect of Intestinal Microbial Ecology on the Developing Brain JAMA Pediatr. 2013;167(4):374-379. doi:10.1001/jamapediatrics.2013.497 Effect of Intestinal Microbial Ecology on the Developing Brain Martha Douglas-Escobar, Elizabeth Elliott, Josef Neu, JAMA Pediatr. 2013;167(4):374-379. doi:10.1001/jamapediatrics.2013.497 Enteric nervous system, providing bidirectional communication between gastrointestinal cells and the central nervous system. Intestinal epithelial cells mediate interactions between gut bacteria and the central nervous system or the immune system. As bacteria (shown in green) in the intestine come into contact with receptors (shown in black) on the intestinal wall cell surface, the receptors transmit signals to the central nervous system via the vagus nerve pathways (curved arrow to central nervous system) and to the immune system (curved arrow) via Toll-like receptor pathways. So maybe instead of sitting in….. We should get out more…..