The Brown FoundationInstitute for Molecular Medicine

Center for Metabolic and Degenerative Diseases

Good Fat vs Bad Fat and Cancer Prevention

Mikhail Kolonin, Ph.D.

Obesity: white adipose tissue overgrowth

OBES

TY

I

I

“Type 3 diabetes”Alzheimer’s disease

Alzheimer’s disease

Healthy years beyond age 65:

BMI (body mass index) > 30 kg/m2 18.4% adolescents

35.7% adults

Obesity growing prevalence impact on health

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

Both excess and deficit of fat tissue leads to disease

Obesity

Lipodystrophy

Diabetes

BMI and mortality

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)