Cell: Reveals the decisive role and molecular mechanism of vitamin B12 in the metabolism and reproductive traits of adulthood in early life

Why do some people have no history of diabetes in their families, but they also develop diabetes when they grow up?

Why do some people who do not consume high-sugar and high-oil foods in their diets also begin to be blessed in adulthood?

Most of these health problems occur after adulthood, is there also a "law on the protection of minors" for diseases?

Whenever we see the occurrence of obesity, diabetes, and even cancer, we often have the habit of finding the cause from recent behaviors, and may have drunk too much alcohol and eaten more meat recently; Or start tracing whether there are the same diseases and phenomena
in the family.

But in fact, in addition to the above two situations, there are many more people who cannot find answers
from their own information, the environment, and their families.

Neither the regulation of innate genes nor the influence of acquired eating habits, so what are the causes of such health problems such as obesity and diabetes?

The answer may be hidden in the early 1,000 days of
life.

Early life refers to the time from the fetal stage of pregnancy to the 2 years of age of the baby, about 1000 days
.

The nutritional status during this period will affect the growth and development of the individual and the health state of adulthood, so it is defined by the World Health Organization as the "window of opportunity" of a person's growth and development, that is, if the human body lacks a certain nutrition during this time, it is likely to lead to a series of diseases
in adulthood.

In 1989, Dr.
David Barker hypothesized the Developmental Origins of Health and Disease (DOHaD) hypothesis
based on a large number of epidemiological studies.

When the uterine environment is unfavorable, such as nutrient deficiency conditions, the fetus needs to predict and adapt gene expression during development to reduce the effects of
adverse environments.

The effects of this adaptive gene regulation may continue throughout the period after birth, eventually leading to the development of disease in adulthood
.

According to the DOHaD hypothesis, scientists began to study and seek the secrets
of metabolism and aging.

In a new study published in Cell Reports on September 20, 2022, Lianfeng Wu's team at Westlake University's School of Life Sciences showed that deficiencies in vitamin B12 (B12) early in life can cause obesity or reproductive defects in adulthood, that is, infertility
.

Early life B12 regulates lipid levels and reproductive capacity in adulthood across time and space and their molecular mechanisms

B12 is an essential micronutrient for organisms that the body cannot synthesize on its own and must be obtained through some exogenous foods, such as meat
.

B12 deficiency is common
in the developmentally active stages of infants and adolescents.

Recent clinical studies have found that the lack of B12 in the mother's pregnancy can induce the child to produce metabolic disorders such as insulin resistance and abnormal lipid metabolism, which indicates that the lack of B12 in the early life will lead to the occurrence
of metabolic diseases in adulthood.

In Wu Lianfeng's team's study, they used Caenorhabditis elegans (nematodes) as a model, and observed that the lack of B12 in early life led to increased lipid levels and a significant decrease
in reproductive ability in adult nematodes.

After the mother's nematodes have consumed sufficient B12, the offspring nematodes can return to normal levels
of lipid content and reproductive ability in adulthood without additional B12 supplementation.

At the same time, the research team found that by supplementing B12 with nematodes at different stages of development, it was only by supplementing B12 early in life that the fat levels and reproductive abilities of nematodes could return to normal
.

Early life B12 determines the organism's adult lipid levels and reproductive capacity

Why does B12 determine lipid content and reproductive levels in adulthood for nematodes?

First, B12 is a key cofactor
in the metabolic pathway of methionine.

Methionine is one of the essential amino acids of the human body, and the methionine cycle metabolism pathway provides a variety of raw materials for the growth of living organisms
.

The research team confirmed that the methionine cycle-SBP-1/SREBP1 signaling pathway is involved in B12's regulation of the metabolism and reproduction of living organisms across time and space, and blocking the methionine cycle activates the sterol regulatory element binding protein SBP-1/SREBP1, causing a significant increase
in lipid levels in nematodes.

Secondly, early life B12 deficiency raises the level of endogenous long-chain polyunsaturated fatty acids, resulting in the accumulation of toxic lipid peroxides in the body, which in turn induces iron death in germ cells and leads to reproductive defects
of nematodes.

Early life B12 affects adult health of organisms through the methionine cycle-SBP-1/SREBP1 signaling pathway

So, what can we do knowing the molecular mechanisms by which early life B12 regulates adult traits? Can these pathways of action be used to find targets that can reverse obesity and infertility caused by vitamin B12 deficiency early in life?

In experiments, the research team found that the use of RNA interference techniques to block SBP-1/SREBP1 and lipid synthesis pathways in the later stages of development, or to supplement nematodes with iron death inhibitors, can partially save the reproductive defects of B12-deficient nematodes, and these results suggest that these molecules are expected to be therapeutic targets for
related adult metabolic diseases.

The causes of metabolic diseases are complex, and the above-mentioned early life vitamin B12 deficiency is one of the multiple causes of obesity and infertility in adulthood
.

The recent findings of Wu Lianfeng's team provide theoretical support for clinically guiding nutrient intake during pregnancy and childhood, and also provide new ideas
for the basic and clinical research of metabolic diseases such as obesity, type 2 diabetes, and polycystic ovary syndrome that may have early origin characteristics.

References