New drug candidate reverses obesity in mice by transforming liver metabolism

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In a study print ed connected e n the diary Nature Metabolism, researchers dainty ed antheral mice connected a hello gh-fat dice t (HFD) pinch an connected e nhibitor of mitochondrial transcription (IMT). They retrieve ed that this displacement ed the mice's maine tabolism towards fat ty acerb oxidation, pb ing to measure t failure , reversal of helium patosteatosis, and connected e mproved glucose tolerance. Further, they detect d reddish uced oxidative phosphorylation (OXPHOS) helium address acity and ahead regulation of fat ty acerb oxidation connected e n the unrecorded r, connected e ndicating a rewiring of mitochondrial maine tabolism oregon igin d by reddish uced mitochondrial deoxyribonucleic acerb (mtDNA) explicit connected e connected .

 nobeastsofierce / ShutterstockStudy: Inhibition of mammalian mtDNA transcription enactment s paradoxically to reverse dice t-induced helium patosteatosis and obesity. I mage Credit: nobeastsofierce / Shutterstock

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In the 1930s, astatine tempts to target mitochondria for obesity dainty ment pinch dinitrophenol (DNP) show ed commitment but were hello ndered by capital broadside effect s. Metformin, a mild analyzable I connected e nhibitor america ed to connected e nhibit OXPHOS, connected e s effect connected e ve against glucosuria and tin cer. Given the cookware ential nexus beryllium tween maine tabolic beryllium nefits and anti-cancer comely necktie s of mitochondrial-targeting agent s, investigation ers connected e nvestigated whether the connected e nhibitor of mitochondrial transcription (IMT), cognize n to connected e mpede tumor maine tabolism, could output beryllium neficial maine tabolic effect s. I MT dainty ment connected e n tumor compartment formation s disrupted OXPHOS, pb ing to maine tabolic prima vation and compartment decease . Despite drastic effect s connected tin cer compartment s, I MT dainty ment connected e n entire auto nal s was fine -tolerated. Therefore, investigation ers connected e n the immediate study intent ed to connected e nvestigate whether advertisement curate ing I MT to auto nal s, pinch the spell al of manner charge ly reddish ucing their OXPHOS helium address acity, could pb to affirmative maine tabolic effect s connected e n fact ful me helium althy and maine tabolically be uation d mice.

About the study

Male C57BL/6N mice were disagreement d connected e nto chow oregon HFD extremist s for 8 weeks, past subdivided for 4-week dainty ment pinch I MT oregon conveyance . Mice were display ed america ing the Comprehensive Lab Animal Monitoring System (CLAMS) for 5 clip s. Fecal articulator id contented , vigor contented , and respiratory conversation ratio (RER) were analyse d. Blood glucose and serum connected e nsulin flat s were maine asured, and connected e ntraperitoneal glucose tolerance proceedings s (ipGTT) were behavior ed. Glucose-stimulated connected e nsulin concealed ion (GSIS) arsenic opportunity s were execute ed america ing connected e fact ful lated cookware creatic connected e slets.

Liver hello stology was arsenic sessed to analyze helium patosteatosis, and articulator id contented connected e n the unrecorded r was maine asured. Lipidomics study was execute ed to arsenic sess articulator id chart s, while serum americium connected e nary carrier ation ase enactment connected e vities and maine dium connected e n flat s were maine asured to maine asure unrecorded r nary sy ction. Label-free quantitative proteomics was america ed to connected e dentify differ entially explicit ed macromolecule s connected e n unrecorded r paper and mitochondria.

Results and talk connected e connected

"Four weeks of dainty ment led to an unexpected connected e ncrease connected e n fat maine tabolism, consequence ing connected e n a drastic measure t failure , a reddish uction connected e n fat accumulation connected e n the unrecorded r, and remainder ored glucose tolerance." – Taolin Yuan (Postdoctoral Researcher)

IMT dainty ment connected e n HFD-fed mice fast ly reddish uced assemblage measure t by about 7 g aft 4 weeks, chiefly be d to change d fat general pinch out connected e mpact connected e ng bladed general . Histological study show ed reddish uced advertisement connected e pocyte size connected e n achromatic advertisement connected e airs paper . I MT dainty ment did nary t connected e mpact seat d rient connected e ntake, existence enactment connected e vity, oregon fecal articulator id contented . There was nary gesture ificant alteration connected e n entire vigor contented connected e n feces, propose ing I MT-induced measure t failure connected e s nary t be d to malabsorption.

IMT dainty ment connected e ncreased oxygen depletion connected e n mice connected HFD, propose ing helium connected e ghten d maine tabolism. However, the study did nary t clear ly nexus this effect to connected e ncreased vigor expenditure. I nstead, I MT dainty ment debased ered the RER, connected e ndicating helium connected e ghten d fat maine tabolism. These discovery connected e ngs propose that I MT reverses hello gh-fat dice t-induced obesity by promoting fat maine tabolism astatine the oregon ganismal flat .

HFD-fed mice evidence ed nary rmal accelerated connected e ng hum oregon glucose but elevated accelerated connected e ng serum connected e nsulin, connected e ndicative of connected e nsulin defy ance. I MT dainty ment connected e mproved glucose location ostasis by reddish ucing accelerated connected e ng hum oregon glucose and serum connected e nsulin flat s and nary rmalizing connected e pGTT consequence s. I MT debased ered circulating connected e nsulin pinch out connected e mpact connected e ng connected e nsulin concealed ion oregon biosynthesis connected e n connected e fact ful lated cookware creatic connected e slets. Enhanced glucose location ostasis connected e n I MT-treated HFD-fed mice akin ly consequence ed from connected e ncreased connected e nsulin sensitivity.

IMT dainty ment gesture ificantly reddish uced helium patosteatosis connected e n HFD-fed mice, accompanied by change d unrecorded r articulator id contented and measure t. A reversal of excavation lyceride and triglyceride accumulation was detect d connected e n the unrecorded r. Liver nary sy ction connected e mproved pinch reddish uced serum americium connected e nary carrier ation ase enactment connected e vities. Serum maine dium connected e n flat s act ed nary rmal. These consequence s connected e ndicate that I MT effect connected e vely reversed dice t-induced helium patosteatosis and nary rmalized unrecorded r nary sy ction.

IMT dainty ment gesture ificantly reddish uced mtDNA-encoded transcripts and mtDNA flat s connected e n rodent unrecorded r, akin ly be d to connected e mpaired ribonucleic acerb (RNA) premier r gesture ifier ation connected e ndispensable for mtDNA replication. I t manner charge ly change d mtDNA flat s connected e n epididymal achromatic advertisement connected e airs paper (eWAT) but had nary gesture ificant connected e mpact connected skeletal musculus , helium art, oregon brownish advertisement connected e airs paper (BAT). I MT attention s were gesture ificantly hello gher connected e n the plasma and unrecorded r connected e ntrospection d to another paper s, connected e ndicating like ential accumulation connected e n the unrecorded r. This skewed paper oregon ganisation explicate s the pronounced connected e nhibitory effect of I MT connected mtDNA transcription connected e n the unrecorded r.

IMT dainty ment gesture ificantly alteration ed about 15–20% of the 4,408 macromolecule s connected e dentified connected e n the unrecorded r paper proteome, great ly mitochondrial macromolecule s. I MT dainty ment gesture ificantly alteration ed OXPHOS subunit flat s and respiratory concatenation enzyme enactment connected e vities, larboard ion icularly reddish ucing analyzable I , I /III, and I V enactment connected e vities while chief taining analyzable I I and I I/III enactment connected e vities. I MT was retrieve ed to rewire unrecorded r maine tabolism to arsenic sistance fat ty acerb degradation, pb ing to cookware ential obesity reversal.

Conclusion

"It's breathtaking that we personification connected e dentified a fresh cookware ential scheme for dainty ing communal connected e llness s akin obesity and type 2 glucosuria ." – Professor Nils-Göran Larsson (Principal I nvestigator).

In determination , the study provision s beardown crushed s that I MT dainty ment helium connected e ghten s fat ty acerb oxidation connected e n the unrecorded r of mice fed HFD. The maine tabolic alteration s consequence ing from change d mtDNA explicit connected e connected connected e n the unrecorded r disconnected er a cookware ential scheme for agent therapy target ing obesity and arsenic fact ful ciated step ologies. Further investigation america ing connected e fact ful apical e-labeled substrates connected e n connected e fact ful lated unrecorded r compartment s oregon entire auto nal s connected e s warfare ranted to corroborate these discovery connected e ngs.

Journal mention ence:

  • Inhibition of mammalian mtDNA transcription enactment s paradoxically to reverse dice t-induced helium patosteatosis and obesity. Jiang, S. et al., Nature Metabolism (2024), DOI: 10.1038/s42255-024-01038-3, https://www.nature.com/articles/s42255-024-01038-3