Is There An Obesity Gene?

Dr. Sears' Blog: Is There An Obesity Gene?

When I first heard about the discovery of a potential obesity gene on the news, I ignored it. After all, a gene only codes for a single protein, and there are about 25,000 genes of which nearly 1,000 seem to be associated with obesity. Nonetheless, I decided to read the research paper in its pre-publication form (1). Even though it is an incredibly scientifically dense paper, rich in genetic jargon, it finally did it begin to make sense.

The protein for which the gene in question codes is called a transcription factor. Transcription factors are the key players in the process of transferring hormonal signals from the surface of the cell to ultimately generate the gene expression of new proteins. As I explained in my book, “Toxic Fat,” nuclear factor-κB (NF-κB) is the transcription factor that turns on the genetic expression of more proteins that leads to cellular inflammation (2).

The transcription factor in this article, known as KLF14, seems to be related to turning on the metabolic responses that lead to insulin resistance, obesity and metabolic syndrome.

Transcription factors have been around for hundreds of millions of years, and they have been highly conserved by evolution because they work so effectively to fine tune gene expression. This might be expected since they are the key players in turning genes “off” and “on” inside the cell. Since they have been around for a long time, this also means that there are natural compounds (usually nutrients) that are instrumental in controlling their activity. For NF-kB (the master regulatory switch for inflammation), it is known that leukotrienes derived from arachidonic acid activate this transcription factor (3,4), whereas omega-3 fatty acids and polyphenols inhibit its activation (5-7). It is very likely the same nutrients may do the same for the activity of the KLF14 transcription factor. From an evolutionary point of view this makes common sense since in less developed organisms (like the fruit fly), the control of fat, metabolism and immunity are found in a single organ known as fat bodies (8).

As I have pointed out in my books, increased cellular inflammation is the first step toward metabolic dysfunction. This is why any decrease in nutrients like omega-3 and polyphenols or any corresponding increase in nutrients like arachidonic acid may be common nutrient control points that dramatically influence our future health. Obviously, as the balance of these nutrients change, their effects on various transcription factors will amplify their impact on gene expression.

A more ominous implication from this study is that the gene mutations that gave rise to increased insulin resistance came only from the mother. This may be the link to understand how fetal programming transmits epigenetic information from one generation to the next. The combination of fetal programming with radical changes in the human diet may well prove to be a deadly combination for our future health and longevity.


  1. Small KS, Hedman AK, Grunberg E, Nica AC, Thorleissson G, Kong A, Thersteindottir U, Shin S-Y, Richards HB, soranzo N, Ahmadi KR, Lingren C, Stefansson K, Dermitzakis ET, Deloukas P, Spector TD, and Mcarthy MI. “Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes.” Nature Genetics doi 10:1038/ng/833 (2011).
  2. Sears B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008).
  3. Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, and Miller YI. “12/15-lipoxygenase is required for the early onset of high-fat, diet-induced adipose tissue inflammation and insulin resistance in mice.” PLoS One 4: e7250 (2009).
  4. Chakrabarti SK, Cole BK, Wen Y, Keller SR, and Nadler JL. “12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes.” Obesity 17: 1657-1663 (2009).
  5. Denys A, Hichami A, and Khan NA. “n-3 PUFAs modulate T-cell activation via protein kinase C-alpha and -epsilon and the NF-kappaB signaling pathway.” J Lipid Res 46: 752-758 (2005).
  6. Zwart SR, Pierson D, Mehta S, Gonda S, and Smith SM. “Capacity of omega-3 fatty acids or eicosapentaenoic acid to counteract weightlessness-induced bone loss by inhibiting NF-kappaB activation.” J Bone Miner Res 25: 1049-1057 (2010).
  7. Romier B, Van De Walle J, During A, Larondelle Y, Schneider YJ. “Modulation of signaling nuclear factor-kappaB activation pathway by polyphenols in human intestinal Caco-2 cells.” Br J Nutr 100: 542-551 (2008).
  8. Hotamisligil GS. “Inflammation and metabolic disorders.” Nature 444: 860-867 (2006).

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About Dr. Barry Sears

Dr. Barry Sears is a leading authority on the impact of the diet on hormonal response, genetic expression, and inflammation. A former research scientist at the Boston University School of Medicine and the Massachusetts Institute of Technology, Dr. Sears has dedicated his research efforts over the past 45 years to the study of lipids. He has published 40 scientific articles and holds 14 U.S. patents in the areas of intravenous drug delivery systems and hormonal regulation for the treatment of cardiovascular disease. He has also written 14 books, including the New York Times #1 best-seller, The Zone, which have sold more than 6 million copies in the U.S. and have been translated into 22 different languages.

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