Why Do We Gain Weight as We Grow Older?

A new study has uncovered key appetite control cells in the human brain that degenerate over time, causing increased hunger and potentially increased weight-gain as people age.

Researchers from Monash University (Melbourne, VIC, Australia) and the Howard Hughes Medical Institute (New York, NY, USA) examined how ghrelin, a hormone that exerts its effect on the brain by regulating neuronal activity, controls the sensation of hunger. They also examined how hunger is sated, when another set of neurons, known as pro-opiomelanocortin (POMC)-expressing neurons kick in, signaling that the stomach is full. Upon examination, the researchers discovered that free radicals created naturally in the body attack the appetite-suppressing POMC neurons after eating, causing their degeneration, and that the effect is more significant following meals rich in carbohydrates and sugars. This creates a cellular imbalance between the need to eat and the message to the brain to stop eating.

The free radicals also attempt to attack ghrelin, which initiates robust changes in hypothalamic mitochondrial respiration; however, these cells are protected by an uncoupling protein (UCP2). The UCP2-dependent action of ghrelin is not yet fully understood, but it is known to be driven by a hypothalamic fatty acid oxidation pathway involving aminopeptidase- (AMP)-activated protein kinase (AMPK), carnitine palmitoyl transferase 1A (CPT1), and free radicals that are scavenged by UCP2. The study was published in the August 14, 2008, issue of Nature.

"People in the age group of 25 to 50 are most at risk. The neurons that tell people in the crucial age range not to overeat are being killed-off,” said lead author Zane Andrews, Ph.D., a neuroendocrinologist at the department of physiology at Monash. "A diet rich in carbohydrate and sugar that has become more and more prevalent in modern societies over the last 20-30 years has placed so much strain on our bodies that it's leading to premature cell deterioration.”

Ghrelin is produced mainly by cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates appetite. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. Ghrelin levels increase before meals and decrease after meals. Ghrelin activates cells in the arcuate nucleus of the hypothalamus, including the orexigenic neuropeptide Y (NPY) neurons, which are both leptin and insulin sensitive. It also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as ethanol.

Related Links:
Monash University
Howard Hughes Medical Institute