Genetic aspects of globesity: Glocalized or not?

Leptin is a protein produced by fat cells (also known as adipose tissue). It travels through the circulation to the brain where the hormone hooks up to a leptin receptor in the hypothalamus to signal to the body that there is enough fat and no more food is needed. In other words, it is a hunger-suppressing hormone. Leptin is sometimes referred to as “Fat Controller”. A congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. In an article in the Journal Genes, the case of two sisters in Colombia who started off their lives as normal weight babies but who quickly suffered from childhood-onset severe obesity was examined. This was the first such case studied from the Americas, while prior cases have studied people whose genetics could be traced back to Pakistan, Turkey, Egypt, India, and China.

What the scientists found is that these two women—now in their 20s—have a mutation in the LEP gene on chromosome 7. Thus, direct sequencing of the coding region of the LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. The sisters’ leptin levels were so low they were below the detection limit of the manufactured test kit. The gene mutation caused the leptin protein to be “misfolded,” rendering leptin ineffective and destroying its function altogether.

When researching the genetics of the family, scientist noted these women were children of lineal consanguinity which means several generations before them married blood relatives. This is a common practice in about a fifth of the world population, mostly in the Middle East, West Asia and North Africa. However, health risks for children of these unions include rare diseases caused by recessive genes.

While more work is needed to figure out how to combat leptin deficiencies on a large scale, the two Colombian women are in the queue to take Metreleptin (Myalept), a synthetic analog of leptin and a very expensive injected drug, as a sort of a hormone replacement therapy. The effects of this therapy can be quite dramatic and life changing. Down the road, one could even imagine that with advanced gene replacement techniques the defective LEP gene variant could be replaced by the fully functioning LEP gene. With obesity now a global problem, scientists around the world are searching for ways to keep the issue from becoming a healthcare burden for years to come.