Genetic Variables Linked to Obesity Are Investigated

The study focuses on the family of uncoupling proteins (UCPs), mitochondrial inner membrane proteins that participate in energy regulation and thermogenesis, among other processes (image: Wikimedia Commons)

Why is it harder to lose weight for some people than others? Why do most, but not all, dieters regain weight? Why do obese patients submitted to the same diet or surgical intervention respond differently to treatment?

To try to answer questions like these, scientists at the Nutrigenomics Research Laboratory (LEN), attached to the University of São Paulo’s Ribeirão Preto Medical School (FMRPUSP) in Brazil, studied the genetic variables involved in weight loss, energy expenditure, and body composition change in obese patients submitted to gastric bypass surgery or diet. The research was supported by FAPESP.

“Several factors are involved in the etiology of obesity, and genetics is certainly one of them. We’re still discovering the pieces of a complex jigsaw puzzle made up of the genes linked to obesity,” said Professor Carla Barbosa Nonino, the head of LEN. “I believe we’ll be able to use this knowledge in the future in an integrated manner to develop more personalized treatments and new drugs.”

The main focus for the group’s research to date has been the family of uncoupling proteins (UCPs), mitochondrial inner membrane proteins that participate in energy regulation, thermogenesis, free fatty acid metabolism, and reactive oxygen species reduction.

“UCP1 is known to be expressed mainly in brown adipose tissue, whereas UCP2 and UCP3 are expressed in various tissues, including white fat and skeletal muscle,” Nonino said.

In a study recently published in the journal Nutrition, the group investigated two polymorphisms of the gene that codes for UCP2, known as Ala55Val and -866G>A, and showed that these polymorphisms could serve as biomarkers of weight loss after bariatric surgery.

The study, conducted during Carolina Nicoletti Ferreira’s PhD research, which was supported by a scholarship from FAPESP, monitored 150 women with grade III obesity (body mass index of 40 or higher) who had been submitted to a surgical procedure known as Roux-en-Y gastric bypass. In this procedure, the stomach volume is restricted to less than 50 ml, and the small intestine is rearranged into a Y-shaped loop so that food bypasses the leftover stomach and duodenum.

“The results showed that one year after the surgical procedure, individuals with a mutated allele, with either polymorphism, presented with greater weight loss, even with adjustment for food intake and regular exercise,” Nonino said.

A paper published by the group in the journal Clinical Obesity showed that the two polymorphisms of the UCP2 gene influenced the food intake of patients who had been submitted to bariatric surgery. “Individuals with at least one mutated allele displayed a tendency to consume more carbohydrate in the assessment performed a year after surgery,” Nonino said.

Another paper by the same group, published in PLOS One, described a study involving 13 patients submitted to surgical intervention. In this study, expression of the UCP1 and UCP3 genes contributed to lipid and carbohydrate oxidation, an important process that allows the substrates to be used as a source of energy instead of being stored as fat.

“There was no change in the expression of these genes after the surgical procedure, but the UCP1 and UCP3 genes were found to influence the oxidation of energy substrates after surgery,” Nonino said. “The more UCP3 was expressed, the greater the carbohydrate oxidation and total oxidation.”

Furthermore, expression of UCP3 influenced the reduction in body mass index and fat mass, as well as the increase in fat-free mass, six months after bariatric surgery. “The greater the expression of UCP3, therefore, the greater the loss of weight and fat mass six months after surgery,” Nonino said.

Another gene investigated by the researchers at LEN is the gene for perilipin 1 (PLIN1). According to Nonino, the protein encoded by this gene coats lipid storage droplets in adipocytes, protecting these droplets until they can be broken down and digested.

In a study published in July in the journal Obesity Surgery, the team at LEN showed that expression of the UCP2 and PLIN1 genes influenced the resting metabolic rate and the percentage weight loss in patients who had undergone bariatric surgery.

“UCP2 and PLIN1 were found to influence the increase in the resting metabolic rate in the pre-operative period when adjusted for weight. Moreover, expression of these genes contributed to an increase in the percentage weight loss six months after bariatric surgery,” Nonino said.

The study also showed that UCP2 expression practically doubled six months after surgery compared with preoperative levels. Expression of PLIN1 was unchanged after surgery.

“The increase in UCP2 expression was linked to the higher resting metabolic rate and could therefore lead to greater weight loss,” Nonino said.

The analyses were conducted during Bruno Affonso Parenti de Oliveira’s research for his master’s degree, which was supported by ascholarship from FAPESP.

Increased expression of UCP2 was also linked to greater weight loss in a study involving obese women submitted to a hypocaloric diet (1200 kcal per day). These results are now available on the European Journal of Clinical Nutrition website. The analyses were conducted during Cristiana Cortes de Oliveira’s master’s research.

The researchers at LEN are also investigating the links between single nucleotide polymorphisms (SNPs) of the UCP1 gene and diseases associated with obesity, such as diabetes. In an article published in the journal Nutrition, for example, they described findings showing a link between a SNP in the UCP1 promoter region (-3826 A/G) and lower weight and less body fat than in individuals without the mutated allele. The researchers also showed that the presence of the mutated allele in homozygosity (inherited from both parents) protected subjects against the development of type 2 diabetes.