‎5 Genes That Make It Hard to Lose Weight, and What You Can Do To Combat Them

BLD026220Do you ever feel like you exercise and eat well, but don’t see positive results? I feel you. I’ve been there! The problem may be with your genes. As scientists look into weight-loss genes, they have found that people with variations of certain genes are more prone to put on weight than others. I know, because I have nearly all of the bad variants! Thankfully, all is not lost: Small tweaks may make your genes work for you, rather than against you.

To date, scientists have discovered seventy-five gene alterations that increase the likelihood of obesity. These genes are usually involved in how the body breaks down food, stores fat, and sends signals to let you know you’re no longer hungry. Variations to these genes are known as polymorphisms.

As a result of genetic variation, two people could eat the same exact diet but put on vastly different amounts of weight. One theory is that people who gain more weight from eating the same amount of calories do so because it was once an evolutionary advantage. Thousands of years ago, food was often scarce, so being able to gain weight from very few calories could have meant the difference between life and death. Now, food is easy to come by. Still, these “thrifty-genes” persist in some people’s genomes.

Lifestyle Effects on Genes

The good news is that even if you have these genetic polymorphism, you can work to combat them with lifestyle practices.  This is because DNA sequences are not the only way that can alter gene expression, rather, epigenetics also plays a role – meaning your lifestyle affects how genes turn on or off.  Here is a list of the five key genes involved with weight gain, and some lifestyle habits that you can implement in order to combat their effects.

1) Food Intake: FTO

One of the most studied obesity genes is FTO (dubbed “Fatso”), which stands for Fat Mass and Obesity Associated. FTO seems to act as a “nutrient sensor,” affecting the amount of food a person wants to eat, and their hunger. Therefore, variations in the gene that encodes for FTO could affect the ability of FTO to regulate food intake and lower satiety. Scientists have found that people with certain variations in this gene have a higher BMI.

What to do?

Increased exercise could counteract the effects of the polymorphism of FTO. For example, the Amish have a high incidence of FTO—yet very few are obese. Why? Because each day, they labor on their farms for two hours or more. The hard physical labor keeps FTO from expressing obesity, making the Amish exemplify how an environmental trigger can modify gene expression. The good news is that you don’t necessarily need four hours of hard physical labor. Many of patients with this gene variant consistently exercise for 30 minutes, five days per week, and it keeps the gene turned off.

2) Fat metabolism: PPARG

Another gene affecting weight gain is the one that encodes for PPARG, a protein involved in fat metabolism. When activated, PPARG creates fat cells and helps with the uptake of dietary fats from your blood. Too much activation of PPARG can cause weight gain and increase the risk for heart disease, diabetes, and stroke. Obese individuals have much higher amounts of this protein in their fat tissue. Individuals with no PPARG have less fat tissue in their limbs and gluteal area.  In addition, studies have shown that post-menopausal women who have a PPARG polymorphism gain more weight than those who don’t.

What to do?
When individuals with the PPARG polymorphism eat more unsaturated fats than saturated fats, they gain more fat tissue and have a higher BMI. By contrast, when they eat more saturated fats than unsaturated fats, the opposite is true—they are leaner. So here again we see how an environmental (meaning non-genetic) factor such as nutrition can trigger a gene and affect people’s weight.

3) Fat breakdown: ADRB2

The adrenergic beta-2 surface receptor gene (ADRB2) codes for a protein that plays an important role in the breakdown of fat. When the hormone epinephrine is released, it can bind to ADRB2 in order to increase energy by breaking down fat molecules. Certain variations are associated with an increased risk of metabolic syndrome in women, a cluster of risk factors that herald a six-fold risk of diabetes mellitus and two-fold risk of cardiovascular disease. Prevalence of metabolic syndrome is higher in middle-aged women than middle-aged men, as well as greater cardiovascular risk. (As a side note, this gene also plays a role in asthma, and response to asthma inhalers.) While more research still needs to be performed to understand its exact mechanism, it seems this gene could be another promising target for understanding the link between genetics and weight gain.

What to do?   

I personally have the polymorphism of this gene, which gives me an increased risk of abdominal obesity. I have about double the difficulty with weight loss compared with people without this polymorphism because my fat mobilization and signal transduction for mobilizing fatty tissue is impaired. All the more reason to eat and exercise efficiently!

4) Efficient Functioning with Methylation (2 Genes): PGC1-alpha and Tfam

Methylation is a chemical process that helps your body to work optimally. Without a healthy rate of methylation, you are at risk for lower metabolism. Methylation is another example of an epigenetic effect in that it doesn’t alter its DNA sequence. Instead, it adds chemical groups to the genes PGC1-alpha and Tfam. In doing so, it changes the rate at which these genes are converted into protein and are involved in creating mitochondria, the powerhouse, energy-creating center of your cells. In these genes, methylation correlates with increased rates of obesity. 

What to do?

Environmental factors such as age, sex, race, exercise, and diet can all produce epigenetic effects and change the amount of methylation in your body. While you obviously don’t have control over your age, race, and gender, here again you can make sure to live a lifestyle of optimal eating and exercise in order to try to combat suboptimal methylation in your body.

You Have the Power

Your genes can make losing weight more difficult—but not impossible. While researchers are still working on understanding the relationship between nutrition and genetics, much is currently known about how other factors like hormones and the microbiome affect weight loss. By living a lifestyle which triggers your body to work best, you can make up for a less-than-ideal genotype.

Modifying genetic expression with lifestyle changes is a key topic in my new book, Younger: A Breakthrough Program to Reset Your Genes, Reverse Aging, and Turn Back the Clock 10 Years, set for release mid-March, 2017. You can benefit from the pre-order price for Younger now, and get ready to learn how to upgrade your lifestyle to compensate for your genes.


Cheng, Z. and Almeida, F. “Mitochondrial alteration in type 2 diabetes and obesity.” Cell Cycle 13 (2014): 890-97.

Goulart, AC, et al. “Association of genetic variants with the metabolic syndrome in 20,806 white women: The Women’s Health Genome Study.” American Heart Journal 158 , no. 2 (2009): 257-62.

Henig, RM. “Fat Factors.” New York Times, August 13, 2006.

Hunt, KJ, et al. “The metabolic syndrome and the impact of diabetes on coronary heart disease mortality in women and men: the San Antonio Heart Study.” Annals of Epidemiology 17, no. 11 (2007): 870-77.

Kolkata, G. “Genes Take Charge, and Diets Fall by the Wayside.” New York Times, May 8, 2007.

Loos, R. and Yeo, G. “The bigger picture of FTO—the first GWAS-identified obesity gene.” Nat Rev Endocrinol, no. 10 (2014): 51-61.

Luan, J, et al. “Evidence for Gene-Nutrient Interaction at the PPARg Locus.” Diabetes 50, no. 3 (2001): 686-89.

Nicklas B, et al. “Genetic Variation in the Peroxisome Proliferator Activated Receptor-g2 Gene (Pro12Ala) Affects Metabolic Responses to Weight Loss and Subsequent Weight Regain.” Diabetes 50, no. 9 (2001): 2172-76.

Saliba, L, et al. “Obesity-related gene ADRB2, ADRB3 and GHRL polymorphisms and the response to a weight loss diet intervention in adult women.” Genetics and Molecular Biology 37, no. 1 (2014):15-22.

Savage D, et al. “Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma.” Diabetes 52, no. 4 (2003): 910-17.

Speakman, JR. “The ‘fat mass and obesity related’ (FTO) gene: mechanisms of impact on obesity and energy balance.” Current Obesity Reports 4, no. 1 (2015):73-91.

Walczak, R and Tontonoz, P. “PPARadigms and PPARadoxes: expanding roles for PPARγ in the control of lipid metabolism.” The Journal of Lipid Research 43, no. 2 (2002): 177-186.

Ruiz, J.R., et al.  “Role of beta(2)-Adrenergic Receptor Polymorphisms on Body Weight and Body Composition Response to Energy Restriction in Obese Women: Preliminary Results.” Obesity 19, no. 1 (2011): 212-15.

Lima, J.J., et al. “Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations.” Metabolism 56, no. 6 (2007): 757-65.


Sara Gottfried MD About Sara Gottfried MD

Sara Gottfried, MD is the author of the new book, Younger: A Breakthrough Program to Reset Your Genes, Reverse Aging, and Turn Back the Clock 10 Years. She's the two-time New York Times bestselling author of The Hormone Cure and The Hormone Reset Diet. After graduating from Harvard Medical School and MIT, Dr. Gottfried completed her residency at the University of California at San Francisco. She is a board-certified gynecologist who teaches natural hormone balancing in her novel online programs so that women can lose weight, detoxify, and slow down aging. Dr. Gottfried lives in Berkeley, CA with her husband and two daughters.