Good Fat vs Bad Fat and Cancer Prevention Mikhail Kolonin, Ph.D. The Brown Foundation Institute for Molecular Medicine Center for Metabolic and Degenerative Diseases 1

Obesity: white adipose tissue overgrowth B E S T Y I Alzheimer’s disease Alzheimer’s disease “Type 3 diabetes”

Obesity growing prevalence impact on health BMI (body mass index) > 30 kg/m2 18.4% adolescents 35.7% adults Obesity growing prevalence impact on health Healthy years beyond age 65: The distribution of body mass index (BMI) is illustrated over time for adult (ages 20‐74 years) (A) men and (B) women by sex and survey year: United States, 1960 to 2008. Body mass index (BMI) is calculated as weight in kilograms divided by height in meters squared. BMI in the range 18.5–24.9 kg/m2 is considered healthy weight (dark green bars), BMI in the range 25–29.9 kg/m2 is considered overweight (medium green bars) and BMI ≥ 30 kg/m2 is considered obese (light green bars). Prevalence was age‐adjusted to the 2000 US standard population using five age groups: 20–34 years, 35–44 years, 45–54 years, 55–64 years, and 65–74 years. Data are from the National Health and Nutrition Examination Survey except data for 1960–1962 which are from the National Health Examination Survey. Source: National Center for Health Statistics. Health, United States, 2010: With Special Feature on Death and Dying (Table 71). Hyattsville, MD. 2011.29 © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party.

Both excess and deficit of fat tissue leads to disease BMI and mortality Obesity Diabetes Lipodystrophy White and brown adipose (fat) tissue Brown Fat Tissue Burns lipids White Fat Tissue Stores lipids Cold Exercise Subcutaneous fat Visceral fat Sedentary life style High-calorie diet Age

Highlights •WAT browning contributes to high energy expenditure in cancer-associated cachexia •Systemic inflammation and IL-6 induce and sustain WAT browning in cachexia •Inhibition of WAT browning ameliorates the severity of cachexia •Cancer cachexia patients stain positive for UCP1 protein in WAT Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limited therapeutic options are available and the underlying mechanisms are poorly defined. Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients.

Nature 513, 100–104 (04 September 2014)