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Abstract
A rising tide of obesity and type 2 diabetes has resulted from the development of
technologies that have made inexpensive high calorie foods readily available and exercise
unnecessary for many people. Obesity and the metabolic syndrome (insulin resistance,
visceral adiposity and dyslipidemia) wreak havoc on cells throughout the body thereby
promoting cardiovascular and kidney disease, and degenerative diseases of the brain
and body. Obesity and insulin resistance promote disease by increasing oxidative damage
to proteins, lipids and DNA as the result of a combination of increased free radical
production and an impaired ability of cells to detoxify the radicals and repair damaged
molecules. By covalently modifying membrane-associated proteins, the membrane lipid
peroxidation product 4-hydroxynonenal (HNE) may play particularly sinister roles in
the metabolic syndrome and associated disease processes. HNE can damage pancreatic
beta cells and can impair the ability of muscle and liver cells to respond to insulin.
HNE may promote atherosclerosis by modifying lipoproteins and can cause cardiac cell
damage by impairing metabolic enzymes. An adverse role for HNE in the brain in obesity
and the metabolic syndrome is suggested by studies showing that HNE levels are increased
in brain cells with aging and Alzheimer's disease. HNE can cause the dysfunction and
degeneration of neurons by modifying membrane-associated glucose and glutamate transporters,
ion-motive ATPases, enzymes involved in amyloid metabolism, and cytoskeletal proteins.
Exercise and dietary energy restriction reduce HNE production and may also increase
cellular systems for HNE detoxification including glutathione and oxidoreductases.
The recent development of low molecular weight molecules that scavenge HNE suggests
that HNE can be targeted in the design of drugs for the treatment of obesity, the
metabolic syndrome, and associated disorders.