Biology subjects

Jacobi, D.

Publications and source records attributed to Jacobi, D..

3 recordsLinked to original sources

bioRxiv2026

Chronopharmacological targeting of mitochondrial dihydroorotate dehydrogenase prevents diet-induced obesity in male mice

Daily hepatic mitochondrial rhythms are strengthened by time-restricted feeding in diet-induced obesity in male mice, as shown by metabolomics, including an early enhancement of oscillations within the de novo pyrimidine pathway. We tested whether timed inhibition of dihydroorotate dehydrogenase (DHODH, which links pyrimidine synthesis to respiratory-chain flux), can reproduce selected TRF-associated mitochondrial and metabolic effects. Administering the short-half-life inhibitor BAY2402234 at dawn transiently decreased DHODH activity, restored daily mitochondrial oxidative dynamics (ubiquinone/ubiquinol ratio), and amplified rhythms of respiratory exchange ratio and mitochondrial dynamics-related markers upon high-fat diet. Under ZT0 dosing, mice showed reduced weight gain, reduced adiposity and hepatic triglycerides, and improved glucose tolerance without changes in food intake; while ZT12 dosing was ineffective. Hepatic Dhodh knockdown did not reproduce the anti-obesity phenotype, and uridine supplementation blunted BAY2402234 benefits, implicating de novo pyrimidine flux. Our findings reveal rhythm-aware DHODH inhibition as a chronopharmacological preclinical candidate approach against overnutrition.

physiology↗

bioRxiv2024

Diurnal regulation of Acyl-CoA synthetase 3 (ACSF3) underlies daily mitochondrial lysine-malonylation and hepatic metabolism

Circadian rhythms are fundamental to maintaining health and are implicated in various diseases. In the liver, daily rhythms are coordinated via the interplay between feeding rhythms and the molecular circadian clock, ensuring metabolic homeostasis. Disruption of feeding rhythms can lead to circadian misalignment, contributing to metabolic disorders, yet the underlying molecular mechanisms remain unclear. Recent evidence suggests that post-translational modifications play a key role in regulating circadian functional output. In this framework, mitochondria serve as a convergence point, integrating rhythms in metabolism, feeding rhythms and the circadian clock. In the present study, we used a multi-omics approach to investigate the role of the Acyl-CoA synthetase 3 (ACSF3) in driving lysine-malonylation and in regulating daily hepatic metabolism. We found that ACSF3 expression and its mediated impact on lysine-malonylation are rhythmic and largely governed by feeding rhythms. While hepatic ACSF3 knockdown did not alter diet-induced metabolic abnormalities, our results demonstrate that ACSF3 plays a role in the diurnal regulation of liver glycogen storage, de novo lipogenesis, and triglyceride synthesis.

physiology↗

bioRxiv2019

Bmal1 integrates mitochondrial metabolism and macrophage activation

Metabolic pathways and inflammatory processes are under circadian regulation. While rhythmic immune cell recruitment is known to impact infection outcomes, whether the circadian clock modulates immunometabolism remains unclear. We find the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-{gamma}/lipopolysaccharide (M1) and tumor conditioned medium, to maintain mitochondrial metabolism under these metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial ROS production and Hif-1-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, the aberrant Hif-1 activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, while administrating an SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1 regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

cell biology↗