Study shows why children of obese moms have inclination to create metabolic illnesses

Overview

• Post By : Kumar Jeetendra


• Source: São Paulo State Research Support Foundation


• Date: 27 Jan,2021

A Brazilian study published in the journal Molecular Human Reproduction helps understand why overweight mothers often have children with a propensity to develop metabolic disease during their lifetime, according to previous research.

According to the authors,”transgenerational transmission of metabolic disorders” may be associated with Mfn2 deficiency in the mother’s oocytes (immature eggs). Mfn2 refers to mitofusin-2, a protein involved in the regulation of vascular smooth muscle cell proliferation. It is normally found in the outer membrane of mitochondria, the organelles that provide cells with energy. A deficiency contributes to mitochondrial swelling and dysfunction, as well as altering the expression of almost 1,000 genes in female gametes.

In the recent book, Chiaratti and his team report the results of experiments with mice genetically modified in order not to express Mfn2 only in oocytes. The Mfn2 deficiency was expected to affect their fertility, but this wasn’t the case. However, their offspring gained more weight than the offspring of control animals and had become diabetic by age 9 months, despite being fed a normal diet.

A number of studies have found mitofusin-2 to be an important metabolic regulator. There’s evidence that weight gain leads to a reduction in levels of the protein in muscle and liver cells, both of which play a key role in regulating blood sugar levels. In the case of diabetics, its expression is reduced in these cells.”

Marcos Chiaratti, Study Main Investigator, Professor, Federal University of São Carlos

Part of this study was conducted during the master’s study of Bruna Garcia in UFSCar’s Center for Biological and Health Sciences (CCBS), with Chiaratti supervising.

The first step was the identification of the type of dysfunction displayed by Mfn2-deficient oocytes on reaching the stage at which they are ready to be fertilized. The study showed a reduced number of mitochondria in these cells and a lesser level of ATP (adenosine triphosphate), the molecule that functions as cell fuel.

The researchers also observed that oocyte mitochondria were more aggregated than normal, enlarged to twice the expected size, and further away from the endoplasmic reticulum, an organelle with which they have to socialize to import calcium and other materials crucial for their functioning.

According to Chiaratti, among the known roles of Mfn2 is ensuring that mitochondria stay in touch with the endoplasmic reticulum, a structure which participates in the synthesis and transfer of many substances in cells. The results of the study imply Mfn2 deficiency compromises interaction between the two organelles, impairing the functions of both in oocytes.

“There is evidence that transgenerational transmission of diseases such as diabetes is associated with mitochondrial dysfunction and endoplasmic reticulum stress in oocytes. Our findings corroborate this theory,” Chiaratti stated. “Mfn2 deficiency seems to affect mitochondrial biogenesis [reducing the amount of mitochondria] and the capacity of mitochondria to move about in the cytoplasm so as to meet cellular demand for energy.”

The next step consisted of characterizing the Mfn2-deficient oocyte’s transcriptome (the full assortment of messenger RNA molecules extracted ) and comparing it with controls. Using RNA sequencing, the researchers found 517 genes which were less expressed in the genetically modified animals’ oocytes than in controls and 426 genes that were more expressed.

We found pathways associated with the functioning of the endoplasmic reticulum and mitochondria, as well as pathways related to endocrine processes such as regulation of blood glucose,” Chiaratti said.

Alterations in offspring
Analysis of the offspring of genetically modified females concentrated on skeletal muscle and liver cells.

Neither muscle cells liver cells have been found to be in endoplasmic reticulum stress, a condition characterized by an accumulation of proteins that impairs the organelle’s functioning, and no mitochondrial alterations were found in muscle cells.

Because this alteration was not sufficient to describe the hyperglycemic phenotype of the offspring, the group chose to study insulin signaling in these creatures, as insulin made by the pancreas enables glucose to enter cells and thereby reduces the level of blood sugar.

Their analysis of pancreas cells showed that insulin production was normal, but the degree of insulin in the bloodstream was reduced and the signal it normally sends to liver and muscle cells was weak.

“In both of these tissues, insulin causes a biochemical change in the protein Akt [protein kinase B]. The signal delivered by insulin makes this molecule become phosphorylated [via addition of phosphate to the protein chain] and this triggers a cascade of biochemical reactions in the cell,” Chiaratti explained.

The results of these analyses, therefore, suggested that the offspring’s muscle and liver tissue received a small amount of insulin, even though the level of insulin production by the pancreas was normal. This increased the hypothesis, to be confirmed in future studies, that insulin was being broken down faster in the organism of these animals.

To deepen their comprehension of the molecular mechanisms that led to augmented weight reduction and hyperglycemia in Mfn2-deficient pups, the researchers plan to replicate the experiment with some alterations. Mfn2-deficient females will be fed with a high-calorie diet to exacerbate the effects of the lack in their offspring.

“We also plan to investigate, in animals with no genetic modification, if it’s the high-calorie diet alone is enough to reduce Mfn2 expression and change the way mitochondria function and interact with the reticulum,” Chiaratti said.

The knowledge generated by these studies, he added, is expected to permit the development of strategies to manipulate Mfn2 expression in the context of obesity and help prevent transgenerational transmission of metabolic disorders.

For Alicia Kowaltowski, a professor in the University of São Paulo’s Chemistry Institute (IQ-USP), a member of Redoxome plus a co-author of this study, the results obtained so far demonstrate that a person’s diet and nutritional status affect molecular shape, one of the factors that influence cellular physiology. Proteins that regulate mitochondrial morphology are therefore potential therapeutic targets and should be explored in future research.

“It should be stressed that we did not find important alterations to the mitochondria in liver tissue even though the animals were diabetic. This accords with other studies showing that mitochondrial function in the liver is highly resilient,” Kowaltowski said. “In our opinion, there must be protection mechanisms in the liver, given its significance to the metabolism. When mitochondrial dysfunction appears in the liver, the reason is the metabolic syndrome has reached an advanced stage of development.”

“Previous research has shown that mitochondrial dysfunction can compromise egg fertility. We created two animal models with which to explore this mechanism in more detail: in one we inhibited expression of mitofusin-1 in oocytes, and in the other, we inhibited expression of mitofusin-2,” Chiaratti said.

Mfn1 deficiency made females infertile, as reported in an article published in The Faseb Journal.

“In this previous study we showed that oocyte-specific Mfn1 deletion altered the expression of 161 genes and influenced several processes in oocytes, over all communicating with ovarian cells,” Chiaratti stated. “In the event of the Mfn2-deficient animals, we observed other alterations in oocytes and offspring, but fertility wasn’t affected. Curiously, the effects of Mfn1 deletion were attenuated in oocytes when Mfn2 was concurrently inhibited, suggesting that the activity of Mfn1 happens after that of Mfn2.”