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Studies help to understand why children of obese mothers are more susceptible to metabolic disorders

Publicado em 26 janeiro 2021

Brazilian study published in the journal _Human reproduction of molecules_ It helps to understand why obese mothers tend to give birth to children who are prone to develop metabolic disorders in their lifetime, as suggested by previous studies.

According to the author, “intergenerational transmission of metabolic disease” may be associated with Mfn2 deficiency in maternal oocytes (immature eggs). Mfn2 refers to mitofusin-2, a protein involved in the regulation of vascular smooth muscle cell proliferation. It is usually found in the outer membrane of mitochondria, the organelles that supply energy to cells. Deficiency causes swelling and dysfunction of mitochondria, altering the expression of nearly 1,000 genes in female gametes.

“Many studies have shown that mitofucin-2 is an important metabolic regulator. There is evidence that weight gain leads to lower protein levels in muscle and liver cells, both of which are important in regulating blood glucose levels. In diabetic patients, their expression is reduced in these cells, “said the study, a professor at the Federal University of San Carlos (UFSCar) and supported by the Sao Paulo Research Foundation (FAPESP). Marcoski Aratti, a senior researcher at the company, said.

In a recent publication, Chiaratti and his group report the results of an experiment with mice genetically modified to not express Mfn2 only in oocytes. Mfn2 deficiency was expected to affect their fertility, but it was not. However, their offspring weighed more than the offspring of control animals and became diabetic by 9 months of age, despite being fed a standard diet.

To investigate the molecular mechanisms associated with this anomalous phenomenon, Chiaratti has established a collaborative study with researchers at the Redoxome and Obesity and Comorbidities Research Centers (OCRC) in biomedicine. Both are research, innovation and dissemination. FAPESP-funded center (RIDC). Part of the study was conducted during Bruna Garcia’s master’s study at UFSCar’s Center for Biohealth Sciences (CCBS), which is supervised by Chiaratti.

The first step was to identify the type of dysfunction that would appear when the Mfn2-deficient oocyte reached the stage when it was ready for fertilization. The analysis showed a decrease in the number of mitochondria in these cells and a decrease in the level of ATP (adenosine triphosphate), a molecule that functions as a cell fuel.

Researchers have also found that oocyte mitochondria aggregate more than normal, expand to twice the expected size, and in organelles that need to interact to import calcium and other functionally essential substances. We observed that it was further away from an oocyte.

According to Chiaratti, one of the known roles of Mfn2 is to ensure that mitochondria remain in contact with the endoplasmic reticulum, a structure involved in the synthesis and transport of several substances within the cell. The results of the study suggest that a deficiency of Mfn2 impairs the interaction between the two organelles and impairs both functions in the oocyte.

“There is evidence that intergenerational transmission of diseases such as diabetes is associated with oocyte mitochondrial dysfunction and endoplasmic reticulum stress. Our findings support this hypothesis,” Chiaratti said. “Mfn2 deficiency seems to affect mitochondrial biosynthesis [reducing the number of mitochondria] The ability of mitochondria to move around in the cytoplasm to meet the energy needs of cells. “

The next step consisted of characterizing the transcriptome (the entire range of expressed messenger RNA molecules) in Mfn2-deficient oocytes and comparing it to controls. Using RNA sequencing, researchers found 517 genes that were less expressed than controls and 426 genes that were more expressed in genetically modified animal oocytes.

“Next, we set out to identify signaling pathways that belong to these differentially expressed genes. Pathologies related to endoplasmic reticulum and mitochondrial function, and pathways related to endocrine processes such as regulation of blood glucose levels. I found it, “said Chiaratti. ..

Changes in offspring

Analysis of genetically modified female offspring with a focus on skeletal muscle and liver cells. The goal was to understand why these animals develop diabetes, even when fed a balanced diet.

Neither muscle cells nor liver cells were found to be in endoplasmic reticulum stress, a condition characterized by the accumulation of proteins that impair the function of organelles, and no mitochondrial changes were found in muscle cells. Hepatocyte mitochondria were moderately dysfunctional.

This change was not sufficient to explain the hyperglycemic phenotype of offspring, so the group decided to study insulin signaling in these animals. The insulin produced by the pancreas allows glucose to enter the cells, thereby lowering blood sugar levels.

Their analysis of pancreatic cells showed normal insulin production, but decreased levels of insulin in the bloodstream, which normally sent weak signals to muscle and liver cells.

“In these two tissues, insulin causes biochemical changes in the protein Akt. [protein kinase B]..The signal sent by insulin phosphorylates this molecule [via addition of phosphate to the protein chain] And this causes a cascade of intracellular biochemical reactions, “explained Chiaratti.

Therefore, the results of these analyzes suggested that progeny muscle and liver tissue received small amounts of insulin, even if the levels of insulin production by the pancreas were normal. This raised the hypothesis that insulin is being degraded faster in these animal organisms, as will be confirmed in future studies.

Next step

To better understand the molecular mechanisms that lead to weight gain and hyperglycemia in Mfn2-deficient puppies, researchers plan to repeat the experiment with some changes. Women who are deficient in Mfn2 are given a high-calorie diet to exacerbate the effects of offspring deficiency.

“We will also investigate whether a high-calorie diet alone is sufficient to reduce Mfn2 expression and alter mitochondrial function and reticulum interaction in non-GMO animals,” Chiaratti said. I will.

The knowledge generated by these studies is expected to enable the development of strategies that can manipulate Mfn2 expression in obese situations and help prevent cross-generational transmission of metabolic diseases. Added.

For Alicia Kowaltowski, a professor at the University of São Paulo Institute of Chemistry (IQ-USP), a member of Redoxome, and co-author of the study, the results so far have been that human diet and nutrition are mitochondrial shapes. Shows that it affects. One of the factors that influence cell physiology. Therefore, proteins that regulate mitochondrial morphology are potential therapeutic targets and need to be investigated in future studies.

“It should be emphasized that even if the animal was diabetic, there were no significant changes in the mitochondria of the liver tissue, which is another indication that the mitochondrial function of the liver is highly resilient. This is consistent with the study, “said Kowartowski. “In our view, given the importance of metabolism, the liver must have a protective mechanism. When mitochondrial dysfunction appears in the liver, the reason is that metabolic syndrome has reached an advanced stage of development. Because there is. “

Infertility and maternal inheritance

A study reported in the latest FAPESP-funded publication through several projects shows how mitochondrial changes, including DNA mutations, are associated with infertility and transmission of diseases across generations. Is part of a research line aimed at understanding.

“Previous studies have shown that mitochondrial dysfunction can impair the fertility of eggs. To investigate this mechanism in more detail, we created two animal models, one. It inhibited the expression of mitochondria-1 in oocytes, and the other inhibited the expression of mitochondria. -2 “said Chiaratti.

Mfn1 deficiency made women infertile, as reported in an article published in _Faseb Journal_..

“This early study showed that oocyte-specific deletion of Mfn1 alters expression of the 161 gene, affecting several processes in oocytes, especially communication with ovarian cells. “Chiaratti said. “In the case of Mfn2-deficient animals, other changes were observed in the oocyte and offspring, but fertility was unaffected. Curiously, when Mfn2 was simultaneously inhibited, in the oocyte It was suggested that the effect of Mfn1 deletion was weakened and the action of Mfn1 occurred. After Mfn2. ”


Mice born to Bruna M Garcia et al, an oocyte-specific deletion of mitofucin 2, gain weight gain and impair glucose homeostasis. _Human reproduction of molecules_ (2020). DOI: 10.1093 / molehr / gaaa071

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Studies help to understand why children of obese mothers are more susceptible to metabolic disorders

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