Genes Can Influence Weight Gain and Obesity... Through the Brain

Frequently, obesity and weight gain are linked to genetics in conjunction with eating habits and activity. Hormones, such as leptin, regulate many different functions in our body, usually either directly through the hypothalamus or through another organ such as the thyroid in conjunction with the hypothalamus. Leptin is a feedback hormone that holds importance in this area of interest, as it maintains homeostasis in adipose (fatty tissue) by regulating thermogenesis (the generation of heat in the body), feelings of satiety and hunger, increase energy expenditure, and the "reward value" associated with certain nutrients in food. Due to this, leptin sensitivity became a focal point for research regarding obesity. 

Dr. Piedras of Loyola University Chicago Stritch School of Medicine recently spoke about her research regarding down-regulating production of KLHL1 proteins, which affect calcium channels in certain types of neurons, resulting in an imbalance of excitatory and inhibitory synapses, favoring inhibitory synaptic activity. In order to better study the effect of a mutant gene that down regulates KLHL1 protein,  Dr. Piedras' team studied wild type mice and mice with a KO mutant neurons (down regulating the KLHL1 protein), and their study found that mice with the KO mutation gained more weight and at a faster pace than the wild type mice upon reaching adulthood, even when fed the same diet. 

Other studies have found similar results when the genes that concern leptin are affected. In the picture above, the mouse on the left is homozygous for a gene that causes insensitivity to leptin in the brain. These (db/db) mice quickly develop type II diabetes and obesity, unlike the mice sensitive to leptin.  

Giving leptin to patients with mutations that cause leptin insensitivity is unlikely to produce positive results. Instead, some scientists are looking into using a direct orexin receptor antagonist. Such a drug would prevent or hinder the release of orexin, which causes feelings of hunger, which may possibly help with treating obesity in patients with leptin insensitivity. Obesity is a multi-faceted problem, and a few of those facets are in the brain. By researching neural pathways and genetics, science can hope to explore the causes of and find chemical solutions for many conditions, including obesity. By using the knowledge we as scientists have, we can explore solutions to our problems and ask the important questions about what comes next, until somewhere in the web of new information we find our solution. Perhaps that next solution will be the regulation of obesity and the genes that cause it, and perhaps that answer to curing obesity does indeed lie in our neurons and the hormones that regulate them. 

Works Cited

"Cell Calcium: down-regulation of endogenous KLHL1 decreases voltage-gated calcium current density." Elsevier. 9 March 2014. 

Scicurious. "Orexin and Binge Eating Rats." Scientific American. Scientific American, 17 Sept. 2012. Web. <http://blogs.scientificamerican.com/scicurious-brain/orexin-and-binge-eating-rats/>.

Piccoli L, Micioni Di Bonaventura MV, Cifani C, Costantini VJ, Massagrande M, Montanari D, Martinelli P, Antolini M, Ciccocioppo R, Massi M, Merlo-Pich E, Di Fabio R, & Corsi M (2012). Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 37 (9), 1999-2011 PMID: 22569505

Image: https://upload.wikimedia.org/wikipedia/commons/0/0b/Fatmouse.jpg