Genetic Obesity: No Matter How Hard You Try, You Have a Setpoint

Genetic Obesity

When a person says that he/ she eats very little but is still gaining weight, They are Not Lying!! For some people, it is hard to lose weight. This is Genetic Obesity where your body has a set point. No matter how hard you try and how much you lose weight, eventually, you will come back to the point where you started.

Can You be Obese or Overweight and Healthy at the Same Time?

Obesity which is known as the main contributor to chronic diseases is now considered a severe public health issue as it increases the risk of heart diseases, diabetes, and even cancer.

Most of the times obesity is considered a chronic energy imbalance, that results from overconsumption of high-calorie meals and physical inactivity.

Obesity and Hypertension (High Blood Pressure)

Other than these lifestyle factors, genes also play a major role in the etiology of obesity. It is said that genes predict how much a person gains weight.

obese but healthy
You can be obese and healthy at the same time!

The setpoint theory of weight suggests that in every person there is a specific set point which is the optimal weight set by the body, in any condition if a patient gains or loses weight the body eventually returns to the set point.

The setpoint is greatly managed by genes. So, all this suggests that genes play a major role in a person’s weight management.

Leading Causes of Obesity and Weight Gain

Genomic research studies of family members, twins, and adoptees suggest that hereditary variables account for a significant amount of adult weight variation.

For example, a major study comparing the BMI of twins raised together or apart found that hereditary characteristics influenced BMI more than childhood environment. [Ref]

How Many Genes Control Your Body Weight?

Since 2006, genomic studies have identified over 50 genes linked to obesity, the majority of which have minor impacts. Several of these genes also have variations linked to monogenic obesity, a pattern that has been seen in a variety of different illnesses.

Obesity appears to be multifactorial, meaning that it is caused by complicated interactions between multiple genes and environmental variables.

Influence of Genes on Energy Balance:

Genes greatly influence the energy balance. After food intake, various signals from the fat tissue, pancreas, and the gut are transmitted to the brain by hormones like leptin, ghrelin, and insulin.

The brain then sends instructions to the body either to consume more and use less energy or the opposite. Any alteration in genes affects their activity levels which then contribute to weight gain or loss.

The main genes that are involved in energy balance include:

  • Adiponectin:
    • Promotes energy expenditure
  • OB Gene:
    • It is involved in the production of the leptin hormone. Any mutation in this gene leads to obesity
  • FTO gene:
    • The Fat Mass and Obesity genes promoted food intake.
  • Insulin-induced gene 2:
    • Involved in the Regulation of cholesterol and fatty acid synthesis

How Genes Influence Genetic Obesity:

Parental obesity is the biggest risk factor for obesity in children. If both parents are fat, the risk increases even more.

Obesity inheritance rarely follows Mendelian patterns, it is caused by a combination of gene mutations, deletions, and single nucleotide polymorphisms.

The majority of instances are polygenic, resulting from the interaction of many genes with a changing environment.

Although each “obesity gene” contributes just a little amount to phenotype, inherited genetic differences collectively play a significant influence in determining body mass and how the body maintains a balance between physical activity and nutrition. Some types of genetic obesity include:

Monogenic Obesity:

This is associated with a mutation in a single gene. Monogenic obesity is defined by early childhood obesity onset, which is frequently linked with other behavioral, developmental, or endocrine abnormalities, such as hyperphagia and hypogonadism. Some causes of monogenic obesity are:

  • Leptin deficiency
  • Leptin receptor deficiency
  • Melanocortin 4 receptor haploinsufficiency
  • Proopiomelanocortin deficiency
  • Proprotein convertase 1

Polygenic Obesity:

This type of obesity is associated with a mutation in multiple genes. This usually occurs when a person’s genetic makeup is vulnerable to an environment that favors energy consumption over energy expenditure.

Syndromic Obesity:

Obesity is sometimes associated with an uncommon but well-known syndrome that includes cognitive delays, dysmorphic traits, and organ-specific abnormalities. Some of these include:

  • Prader–Willi syndrome
  • Fragile X syndrome
  • BardetBiedel syndrome
  • Albright’s hereditary osteodystrophy
  • WAGR syndrome

% Genetic Obesity: No Matter How Hard You Try, You Have a Setpoint

Influence of Diet and Physical Activity on Genetic Obesity:

Epidemiological studies have repeatedly proven that certain diets and lifestyles increase the risk of obesity in those who are genetically predisposed to it.

Studies suggest that sugar-sweetened beverages, fried food consumption, physical activity, and sedentary lifestyles have all been demonstrated to interact with genetic variations in the obesity connection.[Ref]

Types of Obesity: Gynoid Vs Android, Childhood obesity; Grades

Health Professionals Follow-up Study (HPFS) cohorts in the United States suggest that individuals who consumed more sugar-sweetened beverages had a stronger genetic link to obesity than those who consumed less sugar-sweetened beverages.[Ref]

In a meta-analysis, it was suggested that physical activity reduced the impact of FTO variations on obesity in adults. [Ref]

Another study concluded that increased leisure-time physical activity reduced the genetic link, a sedentary lifestyle, as evidenced by excessive TV watching, was found to exacerbate genetic propensity to obesity. [Ref]

Treatment of Genetic Obesity:

The treatment of genetic obesity requires specialized, extensive, and multidisciplinary therapies. Dietary advice and other approaches such as adapted physical activity, speech therapy, psychomotor skills therapy, hormone replacement therapy should be implemented as early as possible.

These measures improve the patients’ condition. The treatment must be done along with the focus on comorbid conditions such as sleep disorders, orthopedic deformities, and cardiac malformations

Nutritional care in Genetic Obesity:

Dietary control is often unachievable in genetic obesity with eating disorders. The adoption of a tight nutritional framework, the restriction of food availability, and the ritualization of food consumption are all methods for preventing obesity, its comorbidities, and the accompanying excess mortality in genetic obesity.

Because uncontrolled eating is a prevalent trait in syndromic obesity, this guideline is also appropriate.

Nutrition for Obesity and Diabetes (Diabesity)

According to one study, in children with MC4R variations, a one-year nutritional and physical exercise program resulted in weight loss equivalent to that of a healthy child.

MC4R variant carriers, on the other hand, returned to their baseline weight within a year of finishing the program. [Ref]

Drug Treatment of Genetic Obesity:

A variety of new therapeutic options have been developed in recent years, particularly for Prader–Willi syndrome and patients with abnormalities in the melanocortin pathway of the MC4R receptor. Some of these are:




Prader-Willi syndromeOxytocin


Significant improvement in behavior and hyperphagia.

Significant weight loss with moderate effect on hyperphagia.

Monogenic leptin deficiencyRecombinant human leptinThis resulted in weight loss and reduction in energy intake
Leptin receptor deficiencySetmelanotideWeight loss and decrease in hunger
Mc4r DefIciencySibutramine



Significant weight maintenance

Weight loss and reduction in hunger

propiomelanocortin defeciencySetmelanotideWeight loss of 50 kg in 2 months

The Role of Bariatric Surgery in the Treatment of Genetic Obesity:

The current research on the effectiveness of bariatric surgery in the treatment of genetic obesity is based on a small number of cases with varied follow-up times.

In one study a sleeve gastrectomy performed on 24 children and adolescents with PWS (resulted in weight loss of 14.7 % in one without complications.[Ref]

In another study, the example of a significantly obese woman who underwent a sleeve gastrectomy was described by a Belgian team. At the three-year follow-up, this resulted in a 32 percent overall weight reduction. [Ref]

Bariatric Surgery Types, Advantages and Disadvantages

Although it results in weight reduction, surgery should be avoided in most cases with syndromic obesity with eating and neurodevelopmental abnormalities, with the exception of unusual cases that must be discussed individually with a multidisciplinary expert team.

Indeed, the benefit-risk balance is mostly negative, due to the poor weight loss outcomes, frequent weight rebound, and, most crucially, the hazards associated with the syndrome’s physical vulnerability of multi-organ damage.

Bariatric Nutrition Guidelines and Assessment ( Before and After Surgery)

Lose weight

What do you think?

Written by Dr. Ahmed

I am Dr. Ahmed (MBBS; FCPS Medicine), an Internist and a practicing physician. I am in the medical field for over fifteen years working in one of the busiest hospitals and writing medical posts for over 5 years.

I love my family, my profession, my blog, nature, hiking, and simple life. Read more about me, my family, and my qualifications

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