Contributing Factors to Obesity — Genetics, Epigenetics, Hormones, and Set Point Theory

In the next few episodes, I want to talk about the contributing factors or causes of obesity in detail. The number one thing is genetics. Genetic predisposition plays a foundational role, influencing metabolic processes, fat storage, and appetite regulation. However, genetics alone do not dictate outcomes. This introduces the concept of epigenetics, which refers to changes in gene expression due to environmental factors like diet, stress, and even prenatal influences. Think of genetics as the blueprint or instruction manual. Epigenetics is like a light switch that turns certain genes on or off.

Dysfunction within neurohormonal pathways disrupts the delicate balance of hunger and satiety signals, metabolic rate, and fat distribution. Hormones like leptin, ghrelin, insulin, and cortisol interact in ways that can drive excessive weight gain when dysregulated. This brings us to the set point theory of body fat mass, which suggests that our body has a predetermined range of fat mass or weight that it naturally tries to defend. Fat mass is a physiologically regulated phenotype, tightly regulated just like body temperature and pH. Obesity results from abnormal regulation of body fat mass, meaning changes in underlying biology lead the body to an elevated fat mass. This is why obesity is a disease.

When you lose weight, your body activates mechanisms to regain it, such as increasing hunger, reducing energy expenditure, and increasing cravings. Adipose tissue is not just a blob of yellow cushiony tissue. It's a powerful and dynamic organ producing over 600 adipokines or hormones, including leptin, adiponectin, resistin, and TNF-alpha. They drive hormone regulation and dysregulation, contributing to metabolic processes involved in appetite regulation, insulin sensitivity, inflammation, and the pathogenesis of heart disease, chronic disease, and cancer. Leptin is the satiety hormone that helps us feel full. However, too much leptin leads to leptin resistance, where the brain becomes resistant to the hormone's message, resulting in reduced satiety, overeating, and weight gain. Research shows that calorie-dense processed foods impair the brain's leptin signaling.

Insulin is another key player. When we eat calorie-dense meals, glucose rises rapidly, making the pancreas pump out insulin. Over time, with too much glucose and fat accumulating, insulin doesn't work as well, resulting in insulin resistance, the precursor to pre-diabetes and type 2 diabetes. Insulin is an anabolic hormone that signals the body to store fat and increase hunger. Other important gut hormones include ghrelin (the hunger hormone), GLP-1 and GIP (satiety hormones targeted by medications like Ozempic, Wegovy, Mounjaro, and Zepbound), glucagon (maintains blood glucose levels during fasting), and amylin (suppresses appetite and slows gastric emptying).

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