How can genes explain an obesity epidemic which has escalated over the past 50 years when our genes haven’t changed? Great question! Let me share a story about how genes and environment shape obesity—and what it means for a kinder, healthier world.
The Heritability of Obesity
Studies of identical twins indicate that 40–70% of obesity is heritable. This means that 40 to 70% of the variability of body weight among the population can be attributed to genetics while the rest is attributable to environmental or behavioural factors.
The Ob Mouse
The story of how we understand the influence of genetics on body weight begins in the 1950s with the discovery of a mutant mouse called the Ob mouse. The Ob mouse is born with an insatiable appetite and subsequently develops obesity.
By the 1990s, researchers discovered these mice lacked a hormone called leptin. In a normal mouse, leptin is released from fat cells and tells the brain they have enough energy and do not need to urgently seek calories.
The Ob mouse demonstrated how disrupted hormonal signalling to the brain led to excessive eating. Initial hopes that this discovery would be the cause and cure of obesity in humans was dashed when we discovered that most people with obesity did not have low leptin levels. Something else was at play.
While the discovery of leptin turned out not to be a game changer for obesity treatment, it opened an important window into understanding common obesity. Leptin pointed us toward a signalling pathway in the deep brain called the leptin-melanocortin pathway. It is in this pathway where dysfunction occurs in obesity.
Monogenic Obesity and the Hypothalamus
The discovery of severe forms of monogenic obesity in humans followed the discovery of leptin including mutation in genes for leptin, the leptin receptor, and another receptor called MC4R.
These discoveries highlighted the critical importance of a deep structure in the brain called the arcuate nucleus that sits in a deep region of the brain called the hypothalamus. It is here that the leptin-melanocortin pathway resides.
The arcuate nucleus is a small but mighty center that is home to two competing tribes of neurons that operate like the “yin” and “yang” of hunger and satiety.
The first tribe is called POMC. When POMC is activated there is an experience of fullness or satiation. The second tribe is called AgRP/NPY. When AgRP is activated, there is an experience of hunger and wanting. POMC and AgRP, depending on strength of the yin/yang signal create an integrated output message to another area of the brain via the melanocortin (MCR) 4 receptor.
What happens when MCR4 is turned on? We can finally feel full, the content of our thoughts shift from food to other important things like building a shelter or organizing our sock drawer. These two sets of neurons in a region about the size of a peanut have a powerful affect on energy balance, caloric intake, and metabolism.
Polygenic Obesity
Later, Genome Wide Association Studies (GWAS) revealed that most obesity was not due to mutations in single genes but instead due to numerous genes passing down to the offspring from the mother and father.
Most cases of obesity are thus polygenic—driven by the combined effect of many genes, each contributing modestly to body weight. But why would these alleles develop and persist?
The Thrifty and Drifty Gene Hypothesis
One theory called the “Thrifty Gene Hypothesis” is that body fatness is selected for over time due to a competitive advantage it may bring to helping survival during famines; however, a more likely theory has been put forward by scientist, Dr. John Speakman called the Drifty Gene. I’ll share this theory with you now as it better explains why some of us are prone to obesity while others are more resistant.
Dr. Speakman and Dr. Hall propose that body weight in individuals has a “lower bounds” and an “upper bounds” or a “dual intervention point”. When we gain too much weight we hit the “upper bound” where there are biological processes that limit further weight gain. The evolutionary reason for this is that too much body fatness would lead to increased risk of predation and lower chances of passing on our genes.
When we lose too much weight we hit the “lower bounds” where we are going to move toward increased caloric intake and reducing metabolism to protect us from further weight loss. The reason for this is that without a strong genetic wiring to preserve mass, we would whither away and die which would also make it impossible to pass on our genes! I hope that makes sense.
So we now turn back to the question, why are there genes in our population that lead to weight gain and what does the “drifty gene hypothesis” say?
Dr. Speakman’s “Drifty Gene Hypothesis” proposes that as humans developed tools, fire, and cooperative defense strategies, the evolutionary pressure to maintain a strict upper weight limit weakened. Without the threat of predation, mutations that allowed for greater body fatness were no longer selected against—leading to genetic drift in the upper bound of body weight regulation.
This relaxed the “upper bounds” which allowed for mutations to be sprinkled into our collective genome with each gene leading to subtle increases in body fatness in a calorie restricted world.
This evolutionary drift explains variability in the upper intervention point between individuals within a population. Some individuals have a much broader zone of “biological indifference” where they don’t experience the upper bound that would limit weight gain—unlike those more prone to leanness.
Gene-Environment Interaction
Obesity is a condition that occurs more often in those who have a broader zone of biological indifference due to an inherited upper intervention point set higher than others. This allows for a broader range of body weight which could explain why some are prone to gaining so much weight in our modern calorie rich environment.
So our inherited appetite system shapes our susceptibility to obesity, while the environment amplifies these vulnerabilities. Our genes set the stage, and today’s obesogenic environment—calorie-dense foods, sedentary lifestyles, other life factors—creates the conditions that drive weight gain in those with genetic predisposition.
Toward a Kinder, Healthier World
From rare monogenic mutations, interplay of genes & environment, theoretic models, obesity research moves us from outdated mythical narratives about obesity (which remain commonplace) to a more accurate & compassionate model. Here we can actually make true headway in reducing suffering.
These insights show why reshaping our environment is critical for preventing obesity. Behavioral interventions can help, but lasting change requires creating spaces that promote healthier choices—limiting exposure to cues that exploit genetic vulnerabilities.
Powerful hormones (leptin) & non-conscious brain centers (MCR4) provide a powerful lower limit that constrains conscious efforts to lose weight which explains why effective treatments are needed to target these circuits beyond focusing solely on healthy behaviours alone.
Understanding the heritability of obesity also challenge obesity bias & stigma. Obesity isn’t a moral failing or a simple “choice.” It’s a chronic disease, rooted in genetic susceptibility and environmental pressures. Compassionate, evidence-based care must replace blame and bias.