Exp Physiol. 2014 Sep;99(9):1241-52. doi: 10.1113/expphysiol.2014.081455.

Advanced onset of puberty after metformin therapy in swine with thrifty genotype.

Astiz S1, Gonzalez-Bulnes A1, Astiz I2, Barbero A3, Perez-Solana1, Garcia-Real I3

1Departamento de Reproducción Animal, INIA, Avda. Puerta de Hierro s/n. 28040 Madrid, Spain

2Unidad de Pediatría. Atención Primaria. Centro de Salud Ciudad San Pablo. Avenida de Madrid, 13 Coslada. 28022. Madrid. Spain

3Departamento Medicina y Cirugía Animal, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria s/n. 28040 Madrid, Spain.

 

Abstract

The prevention and treatment of obesity in children is based in adequate nutrition and exercise plus anti-hyperglycaemic drugs. Currently, the incidence of childhood obesity is aggravated in ethnicities with thrifty genotype, but there is no previous information on the effects of metformin therapy. The relative effects of lifestyle and metformin on patterns of growth, fattening, metabolic-status and puberty-attainment were assessed in females of an obese swine model (Iberian gilts), allocated to three experimental groups (Group-A: obesogenic diet and scarce exercise; groups DE and DEM: adequate diet and opportunity of exercise plus metformin in group-DEM). Group-A evidenced high weight, corpulence and adiposity, high plasma triglycerides and impairments of glucose regulation predisposing for insulin resistance. These features were favourably modulated by adequate lifestyle (group-DE); effects that were strengthened by metformin treatment (group-DEM), which induced an improvement in body development by favouring muscle deposition. However, conversely to expected, metformin advanced puberty onset. Metformin treatments would have positive effects on growth patterns, adiposity and metabolic features of young females from ethnicities developing thrifty genotype or leptin resistance, but negative effects on puberty attainment. This gives a warning to the use of metformin, without further studies, in girls from these ethnicities.

PMID: 25085845

 

Supplement:

Humans, like other species, have coped with cycles of feasting and famine, developing adaptive mechanisms to changing environments in which climate and food availability are the main limiting factors; this is ability to store excess fat and preference for highly energetic foods like sugar and fat: the so-called thrifty genotype (Neel et al., 1962). These patterns have been found in humans but also in other species, mainly carnivorous and omnivorous.

In the human evolution, Neolithic, 12,000 years ago, was a very important shift in the dietary patterns of human beings with domestication of plants and animals, and sedentary lifestyle improving subsistence. Since then, agriculture and animal breeding has changed, especially rapidly during the last centuries, giving way to the current high availability of energetic foods without necessity of intense physical exercise. However, this availability of energetic foods has not been homogenous in all human populations in the world, and some communities or ethnicities have conserved the thrifty genotype until nowadays. Lastly, the current food consumption patterns mainly in the developed countries, often towards diets richer in salt, fat and fast food provides an excess in calories. This situation of food excess and the lack of exercise has become the cornerstone of metabolic disorders associated to lifestyle, like obesity and metabolic syndrome. This scenario becomes more critical in individuals with a marked adaptation to scarcity, such as the previously mentioned thrifty genotype. The mismatching of genetic background with the current “prompt” food excess can enhance the incidence of obesity and related disorders exponentially in some regions in the world (Chen et al., 2012).

Obesity has reached epidemic proportions with recent estimates from the World Health Organization indicating that more than 1.5 billion adults are overweight, and of those nearly 300 million are obese (WHO, 2015). These issues are of utmost relevance in human medicine and therefore a lot of work and epidemiological studies have and are being performed, trying to understand the risk factors and their mechanistic issues. However, mechanistic studies in human cohorts are increasingly challenging due to recognition of a large number of confounders; especially, when long monitoring study periods are intended. Furthermore addressing genetic and environmental interaction in the postnatal period necessitates of complex design and analysis, and finally experimental work can obviously not be performed because of ethical reasons. Therefore research with animal models is needed to understand the mechanisms responsible for the role of particular conditions and neonatal programming for the transmission and suffering of obesity.

Within animal models, research in large animal models offers several advantages when compared to that performed in rodents, such as higher degree of translationality, possibility of taking larger size of samples, application of diagnostic techniques used in human medicine (Bahr and Wolf, 2012).

Moreover, among the different large animal models there is an especially suitable and recommended swine breed for studies on obesity and related disorders: the Iberian Pig. This pig has been facing conditions similar to humans living in developing countries with a background of exposure to harsh environments and food scarcity and an adaptive thrifty genotype giving way to obesity in the event of food excess, because of a characteristic insatiability. In fact, secretion of leptin in the Iberian pig is higher than in other swine genotypes, but the existence of polymorphisms on the LEPR gene coding for leptin receptor causes increased food intake and fat deposition in obesogenic environments, similarly to human obesity (Barbero et al., 2013; Torres-Rovira et al., 2014).

Metformin [3-(diaminomethylidene)-1,1-dimethylguanidine] is an anti-hyperglycaemic drug widely used for the treatment of insulin resistance and glucose intolerance associated to obesity and diabetes and due to its beneficial effects and its safety (Prescrire Int., 2014; Simmons, 2015), is widely used in paediatrics, in obese girls, in combination with adequate nutrition and exercise regimes.

Working with this amenable animal model, we intended to demonstrate the relevance of an adequate lifestyle (adequate food intake and regular moderate exercise) from the early stages of life (during the infancy until puberty) in individuals with a clear propensity to develop obesity (with thrifty genotype). Our hypothesis was that an adequate environment in the life of infants could counteract the genetic/epigenetic propensity of the individuals to obesity. Therefore, normal environments for human were simulated (obesogenic environment, adequate environment, and adequate environment with metformin therapy) with groups of gilts just after weaning.

Our hypothesis was certain, with the group of gilts under a positive environment showing favorably modulated characteristics, when compared to that of the gilts in an obesogenic ambient. Positive effects were also enhanced by the administration of metformin.

But, contrary to our expectations, the group of gilts that received metformin acquired puberty even earlier than the gilts under obesogenic environment. The increased weight and corpulence of metformin gilts, conversely to females in the obesogenic group, were not accompanied by increased adiposity; neither at subcutaneous nor visceral-central depots, with un unexpected enhanced protein deposition triggered by metformin administration. The central precocious puberty has been described in humans and clearly related to an enhanced body weight during prepuberal stages of life and to hipercaloric diets during these phases (Terasawa et al., 2014). However, other factors have also been implicated, such as genetic causes (Macedo et al., 2014) and other nutritional factors as well. Our Iberian gilts show a marked thrifty genotype with a leptin dimorphism for the gen coding for the leptin receptor. Perhaps, these genetic features could be definitive for this dual effect of metformin.

Therefore, these results are relevant in several ways. On the one side, confirming the very positive effects of an adequate environment (diet and exercise) to modulate genetic and epigenetic predisposition to obesity; secondly, confirming the very positive effects of metformin diminishing fat deposition in growing individuals, while enhancing muscle development and body size; but, lastly, giving a warning to the use of metformin without further studies in girls from ethnicities that may have developed thrifty genotype or in girls with some degree of leptin resistance.

 

 ScarcityENvironmenDEF2t

Iberian pigs in a scarce feed-resource environment.

FoodAbundanceIberian pigs in a feed reach environment
 ObeseSaw4

Obese adult sow

 ObeseSow-2

Obese adult sow

 IniaStraw2_crop

Iberian gilts at the farm

 IberianPigMagneticResonanceDEF

Iberian pig undergoing a Magnetic Resonance Scan

 

Contact:

Susana Astiz and Antonio Gonzalez-Bulnes

Comparative Physiology Lab

RA. SGIT-INIA

Avda. Puerta de Hierro s/n

28040-Madrid (Spain)

E-mails: astiz.susana@inia.es & bulnes@inia.es

 

References

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