How to Hack the Genes That Impact Weight Loss & Metabolism

Written by: the Editors of goop


Updated: March 16, 2017


Reviewed by: Dr. Sara Gottfried

How to Hack the Genes That Impact Weight Loss & Metabolism
Dr Gottfried

Something that never seemed fair: Two people can eat the same diet, but one gains weight, while the other doesn’t. Why?

Gynecologist and aging and weight loss resistance expert Dr. Sara Gottfried explains that two factors cause the conundrum: genetics, and how your genes talk to your environment. Far from a sentence of fate, Gottfried has found—with herself, her patients, the thousands of women in her online programs, and through her research on the expanding science of epigenetics and telomeres, conducted for her book Younger—that we have an extraordinary influence over the expression of our genes, and ultimately how they impact our weight. Here, she highlights the genes to know and the lifestyle hacks to adopt to keep your metabolism healthy and your weight where you want it.

A Q&A with Dr. Sara Gottfried


Two people eat the same thing, one gains weight. What’s up?


One theory holds that some people gain more weight than others from eating the same amount of calories because it was once an evolutionary advantage. Food was often scarce for our distant ancestors, so being able to gain weight from very few calories could have meant the difference between life and death. Now, food is plentiful. Yet these “thrifty genes” persist in some people’s genomes, like in the genes for insulin resistance. I have thrifty genes in spades because I’m half Irish (potato-famine genes) and half Ashkenazi Jewish (Pogrom-survivor genes). But even with this kind of genetic polymorphism, you can work to combat gene disadvantages via lifestyle practices.

When two people eat the same diet but respond differently in terms of weight gain, it’s usually the result of two main factors: genetics and how your genes talk to your environment (called GxE, or the gene/environment interaction, in scientific circles). Genes are you, and everything else is the environment: your food, eating habits, hormones, gut health and microbiome, social context, fitness, sense of purpose, toxin exposure, level of inflammation, and even how much you strive and stress. Ninety percent of the signs of aging and disease are caused by lifestyle choices, not by your genes. This is true of obesity and even Alzheimer’s: 90 percent of your risk is from the environment (the way you eat, move, think, and supplement, among other factors), and only 10 percent of your risk is genetic. (I call this the 90/10 rule.)

“You aren’t born with great genes; the science of epigenetics has shown that great genes come from turning genes on and off to your advantage.”

If you feel like you can’t lose weight no matter what you try, genetics may be playing a role, albeit small. The exciting news is that through gene/environment interactions, genes are being switched on and off based on lifestyle cues. You have more control over the way that your genes are expressed than we ever thought possible. Furthermore, you aren’t born with great genes; the science of epigenetics has shown that great genes come from turning genes on and off to your advantage. If you’re struggling with weight gain/weight loss resistance, you want to know about the genes that may be driving you to be more hungry or addicted to carbs, so that you can do something about how those genes are being expressed.


What are the main genes that impact metabolism and weight?


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. 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.

Interestingly, there is a high incidence of this obesity gene among Amish populations—yet very few Amish are obese. Why? In Amish communities, it’s common to labor on the farm for three hours or more per day. Regular physical activity can effectively turn off the FTO gene.

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 postmenopausal women who have a PPARG polymorphism gain more weight than those who don’t.

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, which increases 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 is greater cardiovascular risk. (As a side note, this gene also plays a role in asthma.) 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.

Stress Susceptibility: FKBP5

Genes can make you more susceptible to stress, and age you quicker. (One of the best ways to track the role of stress is to measure telomeres, the molecular structures at the tips of chromosomes that play an important role in biological aging. Research by Elizabeth Blackburn that led to the Nobel Prize in medicine showed that women taking care of a sick child with high perceived stress aged ten years faster than peer controls.) The primary gene, FKBP5, or FK506 binding protein 5, which commands the body’s stress response system, the hypothalamic-pituitary- adrenal (HPA) axis, contributes to slowing down your metabolism.

(If you want to find out about your own genetic makeup: I refer patients and members of my online community to 23andMe.com, which offers a mail-in, home DNA testing kit that uses a saliva sample. After analysis, the results are posted directly onto a personal online account. It’s easy, convenient, and relatively affordable.)


Is there proof that metabolism slows down by age 40 or so?


After age forty, multiple factors converge to create a perfect storm of slow metabolism. The control system for hormones, almost like an intercom in the body, gets wonky. Cortisol goes up. Testosterone goes down, as does muscle mass. Less muscle mass means you have a lower resting metabolic rate and burn calories slower. The loss of muscle mass is gradual and may flow below the radar. By age fifty, the average woman will have lost on average 15 percent of her lean body mass. You lose fast-twitch muscle fibers first (before aerobic capacity), so you may find that jumping rope or doing burpees isn’t what it used to be! An increase in fat can occur between thirty-five and forty, with fat rising 1 percent per year unless you are taking specific action to counter it. Other hormones change, too: You become less sensitive to insulin as you age, leading to higher blood sugar. By age fifty, fasting blood sugar climbs an average of 10 points (in mg/dL). Multiple genes affect your blood sugar. Thyroid function may wane with age, and cortisol may rise. Together, these factors lead to slower metabolism.


What can we can do to counteract this, and influence the genes that have a hand in our metabolism and weight?


There are a few things I do every day to improve the environment for my genes and the health of my metabolism. The scientific term for your environment—the external exposures and their internal effects on the body—is the exposome. Your genes produce specific bio-markers that can be detected in your blood, urine, and hair. Biomarkers indicate the effect of an exposure, susceptibility factors (including genetic susceptibility), and disease progression or reversal. Biomarkers help health professionals accurately measure exposures and their effect, although it’s not necessary to perform expensive testing before you start the inexpensive cleanup of your body.

“You control your exposome by your daily habits of body and mind, both conscious and unconscious.”

You control your exposome by your daily habits of body and mind, both conscious and unconscious, including how often you move and what form that movement takes, what environmental exposures you have in your home and office, what you eat and drink, and how you manage or mismanage your hormones:


Can you share more of your diet recommendations?


Eating is very complex in the way that it interacts with weight. Overall, eating is the largest influence, affecting about 75 to 80 percent of your weight, so it’s the lever to focus on.

I promote a “food first” philosophy, meaning make wiser choices about your intake. Don’t yo-yo diet like I did—it breaks your metabolism. Remove processed foods, refined carbohydrates, sugars, and sugar substitutes from your diet. Eat nutrient-dense foods. Among my top recommendations are:

  • Fermented foods, like cultured vegetables, sauerkraut, and coconut kefir

  • Healthy oils, such as coconut oil, grass-fed butter, chia seeds, flax seeds, and avocados

  • Clean proteins, particularly pastured chickens

  • Low and slow carbs, mainly sweet potatoes, yams, yucca, and quinoa

  • Bone broth (ideally made from wild-caught fish or pastured chicken) to strengthen skin, hair, and nails


You’ve also written about the effect of toxins on our genes and weight—can you explain?


Your exposure to toxic chemicals, pollution, and mold around your home and in your daily life can adversely impact your weight. I have the mold gene (HLA DR), which affects one in four people, and can lead to weight gain due to problems with insulin and leptin. Mold can grow anywhere that is wet and not well ventilated. It circulates your air system and your immune system is supposed to attack it by making antibodies. But if you have a genetic susceptibility, you lack the protection of antibodies, and the toxins get recirculated in your body. This is an unfortunate example of when illness is built into our DNA and, once triggered, the inflammatory response and resulting symptoms can last for years and will continue unless treated. It is often difficult to diagnose a mold illness because the symptoms are extensive and nonspecific, similar to many other conditions: weight gain, memory problems, fatigue, weakness, numbness, headache, light sensitivity; the list goes on and on. You can hire an expert to test for mold at your home or office; and also get a mold-free showerhead.

Polymorphism in the GSTM1, or glutathione S-transferase, gene—which codes for an enzyme that makes the most powerful antioxidant in the body, glutathione—means you could be prone to accumulate mercury. Mercury accumulation can affect your estrogen, thyroid, and brain; and contribute to weight gain. To remedy toxicity, avoid heavy metals: Test your tap water, and swap your household cleaning products for organic, non-toxic versions. Discard any plastic containers and Teflon-lined pans; use glass, ceramic or stainless steel for storing or preparing foods. Pick salmon instead of tuna. Remove any dental amalgams. When choosing makeup, find a clean lipstick to reduce exposure to lead, and select a low-toxicity nail polish.

All these environmental toxins put serious strain on your liver, which works similarly to a chemical treatment facility. When barraged with chemicals from the skin, airways, blood, and the gastrointestinal tract, your body, which is designed to flush out these toxins, works overtime and creates a backup of unprocessed toxins. Too much exposure, too large a backup, and you start to feel more symptoms, and are hit with accelerated aging and illness.

our liver, your body’s natural filter, purifies blood and removes toxins in two phases: garbage generation (phase one) and garbage collection (phase two). In phase one, your liver takes toxins, like mold, out of your blood and converts them into molecules known as metabolites. In phase two, your liver sends the toxic metabolites to your urine or stool. (In other words, you take out the garbage.)

Unfortunately, most of us have a problem with both phases. From stress and constant exposure to toxins, you may have an overactive phase one and create too much garbage—some of which is worse than the original toxin itself. If you don’t help your body to detox, the garbage keeps piling up. The result is that your liver isn’t doing its job of detoxification, which can lead to the symptoms of toxic exposure. By increasing your intake of key minerals, fiber, and other nutrients, you can strengthen the garbage collection and removal capacity of the liver. Moreover, clear out the damage done from exposure to harmful substances, and add in fortifying foods (as mentioned earlier), like broccoli sprouts, Brazil nuts or walnuts to heal your insides, and activate your age-suppressing genes.

Sara Gottfried, M.D. is the New York Times bestselling author of Younger, The Hormone Reset Diet, and The Hormone Cure. She’s a graduate of Harvard Medical School and MIT. Dr. Gottfried’s online health programs can be accessed here.

The views expressed in this article intend to highlight alternative studies and induce conversation. They are the views of the author and do not necessarily represent the views of goop, and are for informational purposes only, even if and to the extent that this article features the advice of physicians and medical practitioners. This article is not, nor is it intended to be, a substitute for professional medical advice, diagnosis, or treatment, and should never be relied upon for specific medical advice.