Genetic aspects of globesity: Glocalized or not?

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June 25, 2019 – The global obesity epidemic is so far-reaching it now has an overarching name: globesity (obviously derived from global obesity).  Very interesting questions arise in this context such as are there glocalized (global and or local) factors involved in this epidemic.

Researchers find new mutation in the leptin gene

Molecular model of leptin.

It is generally accepted that leptin is the key hormone suppressing hunger in individuals. A abnormal low level of leptin could led individuals to eat unlimited amounts of food. A team of researchers from Texas have now just identified a new genetic mutation in the LEP gene that codes for leptin. This new mutation could help researchers understand why people develop excess of body fat. The research is aimed at helping tackle metabolic disorders like cardiovascular disease and diabetes which are fueled by obesity and impact millions of people around the world.

The pinpointing of the protein leptin in the year 2000 was a huge breakthrough in metabolic disease research when this hormone was found missing in rats that randomly became extremely fat in a laboratory setting. Humans also need adequate leptin circulating levels to inform the brain that their body fat content is enough and they do not need to keep eating more food. In other words, leptin signals mammals to stop eating.

Individual with very low leptin, obviously.

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.

See here a short sequence on obesity and leptin:

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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