Why are some people fat and others not?

ORHow 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

0

10

20

30

40

50

60

15-24 25-34 35-44 45-54 55-64 65+

Non-IndigenousAboriginalTorres Strait Islander

Source: McDermott et al, AHR 2003

New and complex: Various theories- all 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 microbiome4. New jobs and leisure: screen time, sitting and

sleep deprivation

Source: Sellayah D, et al “On the evolutionary origins of obesity: a new hypothesis. Endocrinology 2014:doi: 10.1210en.2013-2113

Human migrations and metabolic adaptation to different environmental stressors: a new theory for ethnic obesity variation

Aboriginal adults (Central Australia) 1930s

Torres Strait Islanders, 1930’s-40’s

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

Ethnic differences in BAT volume and activation: Caucasians vs South Asians

Fat ain’t fat

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.

Cold Exposure Thermoneutral Conditions

Source: Lichtenbelt et al. Cold-Activated Brown Adipose Tissue in Healthy Men. N Engl J Med 2009;360:1500-8.

The good news: Cold induces brown fat activity and heat production in lean adults, but much less so in obese adults (the bad news)

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…

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

Composition of the gut microbiota in a neonate is affected by numerous external and internal factors, beginning at birth.

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.

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

So maybe instead of sitting in…..

We should get out more…..