The laboratory run by physiologist José Donato Junior at the University of São Paulo’s Institute of Biomedical Sciences (ICB-USP) has a “hotel for mice” with an impressive variety of animals. In total, José and his team monitor some 1,200 rodents from more than 40 lineages and record the habits and routines of each. Among all the groups, one is particularly noteworthy: overweight mice. It is neither by chance nor due to special diets that these animals weigh three times more than a normal mouse. The obese rodents present a genetic alteration preventing them from producing a hormone that signals to the brain when it is time to stop eating. Without this hormone, which induces satiety — the feeling of fullness — they eat more food than they should and put on weight. The effect produced by this mutation simulates a phenomenon that has begun to be better understood in recent years and may explain, at least in part, why certain groups of rodents, and possibly human beings, have a greater propensity to develop obesity and diabetes: metabolic programming.
The concept indicates that the environment to which the young are exposed during gestation and just after birth influences the development of certain areas of the brain, such as those responsible for controlling hunger and satiety, and favor the onset of diseases in adult life. In an April article published in the journal Nature Reviews Endocrinology, Donato analyzed 161 papers on the matter and consolidated evidence on how this phenomenon is related to the development of obesity and diabetes. “The quest to understand this concept is important because cardiovascular diseases, for which obesity and diabetes are risk factors, are the main causes of death around the globe,” says the physiologist.
The studies, which include data from experiments with rodents and observations of human beings, indicate that, at least in the case of diabetes and obesity, metabolic programming comes about through the release of a group of chemical compounds known as adipokines. Produced by adipose (fat) tissue cells, adipokines function as hormones. Through the blood, they arrive at the brain of the fetus in gestation and influence the formation of areas linked to regulation of hunger, satiety, and energy expenditure. After birth, as adipokines are transferred via breast milk or produced by the newborns themselves, they continue to modulate the maturing process of these brain areas and other body tissues.
In both situations, they may act at both cell and molecule level. In the first, adipokines modify the connections between cells, altering the brain circuit structure. In the second, by means of epigenetic mechanisms, they activate or deactivate important chains for the function of these cells. “Metabolic diseases may also be caused by epigenetic markers, which form throughout life and are passed from generation to generation,” says biologist Patrícia Boer, a researcher at the University of Campinas (UNICAMP) and president of DOHaD Brasil (Developmental Origins of Health and Disease).
Of almost ten adipokines identified to date, two — leptin and adiponectin — are known to play an essential role in metabolic programming that may cause obesity and diabetes. Identified in 1994, leptin is one of the hormones that regulate hunger and satiety in human beings from childhood, and it signals the brain when the body has ingested sufficient food and is ready to expend the accumulated energy. Interestingly, obese people produce higher levels of leptin. This happens because the brain loses its sensitivity to the action of this hormone: so-called leptin resistance. As a consequence, obese people eat more than they should and expend less stored energy, creating a store which is transformed into fat, something very similar to what happens with insulin in type-2 diabetes cases.
As the fetus develops, however, this hormone acts in two ways. When the expectant mother is obese, her organism produces large amounts of leptin, much of which is transferred to the fetus. When abundantly exposed to leptin, brain regions that should pick up on the presence of this hormone become insensitive to it. In principle, this organism would normally be programmed to resist leptin and, consequently, store more energy in the form of fat, with the potential for developing metabolic diseases such as obesity and diabetes. The young of mothers with lower-than-ideal weight are less exposed to leptin during gestation, and the brain does not learn to identify the action of the hormone; it is as if it doesn’t exist for them, as occurs in obese mice in Donato’s laboratory. Both the young of obese mothers and those below ideal weight have the same propensity to become obese and contract diabetes during their lives.
For Cristiane Matté, a biochemist at the Federal University of Rio Grande do Sul (UFRGS), what happens with young rodents of very slim mothers reminds her of a population study focused on the descendants of expectant Dutch mothers who suffered from hunger during the Nazi invasion in 1944. Coordinated by epidemiologist Tessa Roseboom of the University of Amsterdam, the study showed that dietary restriction among mothers permanently affected the structure of the organs of their children, who, on reaching adulthood, developed kidney, respiratory, mental-health, and metabolic issues, particularly obesity. This effect was passed down from generation to generation, with an impact on public health in the country for decades, as reported by researchers in a 2021 article published in the journal BMJ Open.
“Mothers whose nutritional intake was extremely restricted in the third quarter of pregnancy gave birth to babies with a thrifty phenotype,” explains Matté, a researcher at the UFRGS Center for Metabolic Programming Studies, and a member of the DOHaD Brasil Association. “These children were born when the war was already over, but their metabolisms were programmed for a situation of scarcity, and to make maximum use of the carbohydrates, lipids, and proteins to which they had access.”
The concept of thrifty phenotypes was created by English epidemiologist David Barker (1938–2013) after he observed that children born below ideal weight died later from cardiovascular diseases caused by other metabolic issues. Subsequent studies into rodents demonstrated that exposure to low levels of leptin in gestation or just after birth, a similar situation to that of mothers experiencing severe food deprivation, gives rise to changes favoring the onset of diabetes and obesity in adulthood.
The other hormone highlighted by Donato in the Nature Reviews Epidemiology article is adiponectin, which programs the metabolism of the fetus differently. Instead of influencing brain development, as leptin does, adiponectin acts upon access to nutrients, with an impact on baby size at birth. It increases liver and muscle cell sensitivity to the hormone insulin, which uses glucose as a source of energy.
Expectant mothers with diabetes generally have low levels of adiponectin in their blood and, as a result, high concentrations of glucose. With more nutrients available, their babies are born bigger than expected for the gestational age. The opposite occurs in expectant mothers experiencing hunger: levels of adiponectin in the blood are high, with low levels of glucose. With less access to this nutrient, the fetus develops less and the baby is born at a lower weight than considered healthy. In both situations, however, the outcome is similar: there is a considerable increase in the risk of developing obesity, diabetes, and cardiovascular diseases in adulthood. Barker was the first to make this association — the so-called Barker hypothesis — between size at birth and the risk of developing these illnesses. “Fetal growth alterations are important in increasing or reducing the risk of subsequent diseases,” says Donato. Data on birth size are easily accessible in several countries, which has enabled more research into this relationship.
Léo Ramos Chaves / Revista Pesquisa FAPESP“Hotel for mice” of ICB-USP, where researchers monitor more than 40 lineages of rodentsLéo Ramos Chaves / Revista Pesquisa FAPESP
Laboratory experiments on rodents, such as that conducted by Donato, help to provide insight into what happens in the human organism. “We know that all leptin physiology is identical in people and animals,” confirms the researcher. One advantage of studies into rodents is that their gestation only lasts 21 days, enabling researchers to observe in a few days or weeks what could take years for human beings.
This knowledge could be useful in informing people that metabolic diseases during pregnancy could be as harmful to the fetus as drinking alcohol or smoking. “This is not so obvious to the population, and knowing it allows parents to plan for weight loss and control diabetes before they have a child,” Donato concludes. “It is paramount to be more disciplined in weight and nutrition control during the prenatal stage.” The long-term expectation is that studies will inspire new therapies to prevent babies from becoming adults with metabolic diseases.
Although it could explain some obesity and diabetes cases in adult life, metabolic programming should not be seen as a permanent sentence on future health. These diseases are multifactorial, and can be caused by external influences, but also by genetic or epigenetic heritage. “If the causes were solely genetic, only 5% of the population should be obese, for example, but the numbers are much higher,” says Lício Velloso, Professor of medicine at UNICAMP. Access to a quality diet also has an influence on the onset of metabolic diseases and should be encouraged by public policies and health professionals, especially for expectant mothers, say the researchers.
However, metabolic programming does not always have negative consequences. “In studies with rodents, females that undertook frequent exercise during gestation had offspring who also practiced more physical activity,” reports Matté, of UFRGS. “In other words, exercise can leave an imprint for life. In such cases, this would be metabolic programming for good.”
Researchers estimate that, in humans, metabolic programming may occur until at least the second year of life. “The first thousand days of development, which start on conception and go to the second year, are effectively the period of greater organ plasticity and metabolic adaptation to outside influences,” the researcher explains. “Everything that happens during this period impacts the health of the individual throughout their life,” concludes Matté.
Projects
1. The central nervous system as a growth hormone target for regulating multiple biological functions (nº 20/01318-8); Grant Mechanism Thematic Project; Principal Investigator José Donato Junior (ICB-USP); Investment R$1,616,023.74.
2. CMPO – Multidisciplinary Center for Research into Obesity and Associated Diseases (nº 13/07607-8); Grant Mechanism Research, Innovation, and Dissemination Centers (RIDC); Principal Investigator Licio Augusto Velloso (UNICAMP); Investment R$28,596,577.04.
Scientific articles
DONATO, J. Programming of metabolism by adipokines during development. Nature Reviews Endocrinology. Online. apr. 13, 2023.
BLECKER, L. S. et al. Cohort profile: The Dutch famine birth cohort (DFBC) ‒ A prospective birth cohort study in the Netherlands. British Medical Journal Open. Online. mar. 4, 2021.
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