The genetics of fat regulation—and how it helps polar bears

Whether you’re a hibernating polar bear or a human, you need fat. Fats help build hormones, they help us survive famines, and they help us maintain a consistent body temperature. But storing too much fat can be a problem, which is why a healthy balance of fats in our diet is important. It’s been known for over a century that a person’s body weight is influenced to some extent by heredity. Nowadays, we’ve come to learn that genetics do play an influential role in determining a person’s body mass index (BMI), and that changes in the DNA can result in a person retaining more fat compared to others. Among the many variants linked to a high BMI, variants in the Fat Mass and Obesity Associated gene (FTO for short) stand out due to their well-studied link with body fat regulation.
Weight gain occurs when the amount of energy we consume is greater than the amount of energy we use. Our bodies have evolved to produce body fat as a method to hold onto highly energetic molecules (like sugars and fats) when they’re consumed in excess. Such mechanisms helped our ancestors survive during times of famine, but now this adaptation contributes to the rising number of people—nearly 34.9% of American adults—who are classified as obese1.

Unbearable cold Brown fat is critical for hibernating animals9. Research has shown that this type of fat helps them maintain body heat when waking from their slumber in colder climates.
Research into the genetic differences between polar bears and their southern relatives—brown bears—suggests that polar bears have variants in the FTO gene region which may increase the amount of stored white fat and help them survive the cold!10

In an effort to better understand what factors contribute to weight gain and obesity, scientists studied the genomes of large numbers of people to identify genetic variants that appear to be associated with BMI. These studies have found hundreds of independent genetic variants associated with different measures of body fat. While many genes with many different functions contribute to this body fat, the first variants unequivocally and reproducibly linked to body mass are in the FTO gene2,3.
Originally, variants in the FTO gene were thought to affect body weight by somehow altering the activity of the FTO gene. But more recent evidence showed that a key variant in FTO actually affects genes that are located next to it in the genome4. These genes play a role in determining the types of fat that we store. Animals have different kinds of fat tissue which have been categorized as “white fat,” “beige fat,” and “brown fat.”5 There are many differences between the types of fat, but an important distinction is their role in fat storage and use:

• White fat stores and releases excess fat, and is associated with higher body weight.
• Brown fat stores and continually breaks down excess fat, and is associated with lower body weight.
• Beige fat stores and breaks down excess fat when prompted by the body, and is associated with lower body weight.

Both brown and beige fat have large amounts of mitochondria which break down excess fats and release energy in the form of heat. Brown fat is continually generating heat, while beige fat only does so when stimulated by the body in response to norepinephrine, exercise, or cold temperatures. This is one mechanism that our body developed to help us survive cold weather: sensors in our skin detect cold temperatures which relay a signal back through our brain and onward to the brown and beige fat to increase heat production. In fact, there’s evidence that suggests some human populations evolved the ability to retain higher amounts of brown fat, which allowed them to survive in cold climates like Greenland6. Similarly, some populations of humans developed the ability to insulate their body by retaining high amounts of white fat—an ability that may have been gained due to changes in the DNA coding for the FTO gene4.

Howdy, neighbor The DNA surrounding a gene can affect how and when the body uses it. Sometimes, two genes are in very close proximity, which means that changes to one gene can affect the other.
One important variant in the FTO gene has been shown to influence body weight by affecting two genes (known as IRX3 and IRX5) that are very close by. Both of these genes play an important role in determining what type of fat you make4.

Variants in FTO have been shown to be strongly associated with higher BMI and increased consumption of fats3,7,8. This association may be due to one variant in particular that decreases the body’s ability to make beige fat in response to a high-fat diet. An inability to make beige fat may result in higher levels of white fat and a higher fat mass. Research has shown that people who inherit specific variants in the FTO gene are more likely to have higher fat mass when compared to people without these variants (people in the studied population with two copies of the variants were, on average, 3 kg heavier than people without these FTO variants)3,7. Based on this research, some products offered in the Helix Store like Fitness Diet Pro, embodyDNA, and MyTraits Sport look at the FTO gene to help you understand how your body is likely to process and retain some fats.
Polar bears may not need to think about their genetics or their fat composition very often—but for us humans, knowledge is power! Studies have explored whether a person’s DNA can influence the effectiveness of a diet and found that people who inherited certain variants in the FTO gene required more exercise to maintain a similar body weight compared to people without these variants7. Simply because you’ve inherited a variant that increases your odds of having a higher BMI does not mean that you will have a high BMI, and similarly, the lack of these FTO variants does not mean you won’t gain weight. But understanding what genetic variants you’ve inherited and how these may influence your body weight can help you understand more about yourself, and that understanding may help motivate you to pursue a healthier lifestyle.

1Castillo, Joseph J., Robert A. Orlando, and William S. Garver. “Gene-Nutrient Interactions and Susceptibility to Human Obesity.” Genes & Nutrition 12 (2017): 29. PMC. Web. 17 Jan. 2018.
2Loos, Ruth J.F., and Giles S.H. Yeo. “The Bigger Picture of FTO – the First GWAS-Identified Obesity Gene.” Nature reviews. Endocrinology 10.1 (2014): 51–61. PMC. Web. 17 Jan. 2018.
3Fawcett, Katherine A., and Inês Barroso. “The Genetics of Obesity: FTO Leads the Way.” Trends in Genetics 26.6 (2010): 266–274. PMC. Web. 17 Jan. 2018.
4Claussnitzer, Melina et al. “FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.” The New England journal of medicine 373.10 (2015): 895–907. PMC. Web. 17 Jan. 2018.
5Harms, Matthew, and Patrick Seale. “Brown and beige fat: development, function and therapeutic potential.” Nature News, Nature Publishing Group, 29 Sept. 2013, www.nature.com/articles/nm.3361.
6Marciniak, Stephanie, and George H. Perry. “Harnessing ancient genomes to study the history of human adaptation.” Nature Reviews Genetics, vol. 18, no. 11, Nov. 2017, pp. 659–674., doi:10.1038/nrg.2017.65.
7Sonestedt, E, et al. “Association between fat intake, physical activity and mortality depending on genetic variation in FTO.” International Journal of Obesity, vol. 35, no. 8, 2010, pp. 1041–1049., doi:10.1038/ijo.2010.263.
8Corella, Dolores et al. “A High Intake of Saturated Fatty Acids Strengthens the Association between the Fat Mass and Obesity-Associated Gene and BMI.” The Journal of Nutrition 141.12 (2011): 2219–2225. PMC. Web. 17 Jan. 2018.
9Morin, Pier, and Kenneth B. Storey. “Mammalian hibernation: differential gene expression and novel application of epigenetic controls.” The International Journal of Developmental Biology, vol. 53, no. 2-3, 2009, pp. 433–442., doi:10.1387/ijdb.082643pm.
10Miller, Webb et al. “Polar and Brown Bear Genomes Reveal Ancient Admixture and Demographic Footprints of Past Climate Change.” Proceedings of the National Academy of Sciences of the United States of America 109.36 (2012): E2382–E2390. PMC. Web. 17 Jan. 2018.