Study reveals key mechanism behind obesity-related metabolic dysfunction

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In a recently published study, Dr Nature is metabolicResearchers found that high-fat diet (HFD) feeding caused mitochondrial dysfunction and fragmentation in white adipocytes of mice.

Study: Obesity causes mitochondrial fragmentation and white adipocyte dysfunction due to activation of RalA.  Image credit: Kateryna Kon/Shutterstock.com
Study: Obesity causes mitochondrial fragmentation and white adipocyte dysfunction due to RalA activation.. Image credit: Kateryna Kon/Shutterstock.com

Background

Obesity has become a global epidemic, increasing the incidence of non-alcoholic steatohepatitis, diabetes and other cardiometabolic disorders. White adipose tissue (WAT) is chronically enlarged during the development of obesity, with metabolic changes characterized by fibrosis, inflammation, hormone sensitivity, and apoptosis. Mitochondrial function is impaired in obese individuals and the underlying mechanisms and their contribution to obesity remain unclear.

Research and results

In the current study, researchers demonstrated increased expression and activity of Ras-like proto-oncogene A (RalA) in adipocytes from obese mice and reduced HFD-induced obesity in the target group. Rala Removed in white adipocytes. First, they mentioned Rala Epididymal (eWAT) and inguinal WAT (iWAT) adipocyte expression during obesity development in HFD-fed rats relative to controls.

Furthermore, Rala protein levels were increased in IWAT adipocytes from obese mice. No changes were observed in RalA in brown adipose tissue (BAT) after HFD feeding. Next, RalA-floxed (Ralaf/f) mice and adiponectin-promoter-driven Cre transgenic mice were crossed to generate adipocyte-specific Rala Knockout (KO) mice (RalaAKO) RalaAKO Mice have 90% reduced RalA protein in primary adipocytes from BAT and WAT Ralaf/f littermate

RalA depletion reduces insulin-stimulated glucose uptake in BAT and iWAT. In addition, brown adipocyte-specific KO mice (RalaBK also) is produced by crossing Ralaf/f mice and uncoupling protein 1 (Ucp1)-promoter-driven Cre transgenic mice. This results in decreased glucose uptake in BAT RalaBK also mice, and insulin-stimulated glucose uptake was restricted mainly to brown fat.

Adipocyte-specific Rala Mice fed a deleted chow-diet (CD) did not affect body weight, although they lost fat mass and depot weight. RalaAKO Mice had smaller iWAT adipocytes than CD-fed controls. RalaAKO Rats fed 60% HFD lost weight compared to controls. HFD-feeding RalaAKO Rats had smaller adipocytes in iWAT but not in BAT or eWAT compared with controls.

HFD-feeding RalaAKO Mice also showed improved glucose tolerance without changes in insulin tolerance; They reduced insulin levels and assessed the improved homeostasis model of insulin resistance (HOMA-IR) compared to controls. RalaAKO Mice with downregulation of hepatic gluconeogenic genes showed reduced glucose excursions in a pyruvate tolerance test compared to controls.

HFD-feeding RalaAKO Rats had lower triglyceride levels and lower liver weight and liver lipid accumulation than controls. Moreover, the expression of lipogenic, fibrosis-related and inflammatory genes was reduced in the liver. RalaAKO The mice team found that adipocytes Rala Cd feeding did not abolish food intake and energy metabolism in rats.

However, HFD-fed RalaAKO Rats have increased energy expenditure. In contrast, energy expenditure and food intake were identical in the HFD-fed RalaBK also mice and controls, suggesting that the WAT-specific Rala Reduced energy costs. Furthermore, oxidative phosphorylation proteins were upregulated in IWAT RalaAKO mice but not in eWAT.

Next, the team explored the mechanisms underlying the increased energy metabolism RalaAKO Rat and mitochondrial activity in adipocytes. They observed an elevated oxygen consumption rate in iWAT mitochondria from KO mice relative to controls. Furthermore, fatty acid oxidation was higher in KO adipocytes. Expression of mitochondrial biogenesis-related genes in WAT was comparable between HFD-fed RalaAKO And Ralaf/f the rat

Electron microscopy showed that HFD feeding of wild-type mice induced small, round iWAT mitochondria. iWAT mitochondria in CD-fed mice had an elongated shape, while HFD-fed mice had smaller mitochondria. Also, adipocytes Rala Ablation in the IWAT of CD-fed mice did not grossly affect mitochondrial morphology; In contrast, HFD-induced morphological changes in mitochondria were prevented Rala KO iWAT.

Mitochondrial morphology was unchanged in BAT Rala Deletion in HFD- or CD-fed mice. HFD reduces protein levels of long and short forms of optic atrophy 1 (Opa1), a mitochondrial fusion regulator, in iWAT. However, only the short form (S-Opa1) was upregulated in eWAT. Further, they focused on dynamin-related protein 1 (Drp1), which regulates mitochondrial fission, and increased phosphorylation at the anti-fission site (S637). Rala KO iWAT.

The researchers analyzed WAT’s microarray data from non-obese and obese women to examine the relevance of Drp1 in human obesity. They found that the human Drp1 homolog, dynamin 1-like (DNM1LHOMA-IR and body mass index were positively correlated. DNM1L Expression was upregulated in obese subjects.

Conclusion

Taken together, the study showed that RalA was induced and activated in white adipocytes of HFD-fed mice. Targeted RalA deletion in white adipocytes prevented obesity-associated mitochondrial fragmentation and prevented HFD-induced weight gain through higher energy expenditure.

HFD-feeding RalaAKO Rats have improved liver function and pyruvate tolerance and reduced gluconeogenesis and hepatic lipids. Overall, chronically increased RalA activity plays a role in suppressing energy expenditure in obese adipose tissue by shifting mitochondrial dynamics toward excessive fission and contributes to weight gain and metabolic dysfunction.



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