Biology subjects

Palani, N. P.

Publications and source records attributed to Palani, N. P..

3 recordsLinked to original sources

bioRxiv2025

Sex Hormone Binding Globulin Controls Gender Specific Lipolytic Activity in Human Abdominal Subcutaneous Adipocytes

Regulation of lipid metabolism is fundamental for metabolic health, and adipose tissue is a central component in this process. Adipose tissue differs dramatically between women and men with a higher subcutaneous capacity for storage and healthy metabolism in women. Sex hormone-binding globulin (SHBG) contributes to the regulation of circulating sex hormone bioavailability and has been shown to predict risk of metabolic dysfunction. We here investigate the sex-specific relationship of SHBG with metabolic status and adipocyte-dependent lipolysis. We measured serum concentrations of sex hormones, SHBG, fasting glucose and insulin in a cohort of 63 women and 27 men from which adipose biopsies were collected and mature adipocytes were isolated. We found that, in women, high serum SHBG concentrations were strongly associated with low HOMA-IR in vivo, and lower baseline lipolysis but higher responsiveness to isopropanol-induced lipolysis ex vivo. In contrast, no effect of SHBG on the above-mentioned parameters were observed in men. In vitro, cultured adipocytes also increased lipolytic capacity in response to SHBG, but only in the absence of testosterone, suggesting that testosterone inhibits the catecholmine-induced lipolysis of SHBG in adipose tissue. In conclusion, we here define a novel role for SHBG in adipocyte lipolysis. At the same time, our data emphasize sex-dependent differences in adipocyte lipid metabolism, and we propose testosterone binding to SHBG as a driving factor mediating these differences.

physiology↗

bioRxiv2024

Contact-based thymidylate transfer promotes collective tumor growth

Sustained cell proliferation is a fundamental hallmark of cancer, yet its mechanism remains elusive, particularly in context of heterogenous tumor organization, intercellular interactions, and metabolite exchanges. In this study, we uncover a mechanism of tumor growth via collective proliferation, where cells connected by gap junctions enable equilibration of thymidylate (dTMP) to allow the proliferation of cells lacking canonical de novo dTMP biosynthesis and salvage driven by thymidylate synthase (TYMS) and thymidine kinase 1 (TK1) enzymes, respectively. Collective proliferation is driven by dTMP-proficient cancer cells alongside cells of varied origins, such as macrophages and endothelial cells. The mechanism is also observed in clinical samples and is validated in a genetic mouse model of lung cancer harboring dual Tyms/Tk1 tumor-specific knockout, in which tumors grow despite lacking enzymatic dTMP synthesis and tumor progression is opposed by gap junction inhibition. Data further hint that this mechanism is critical driver of tumor pathophysiology, influencing key processes such as senescence, genomic instability and drug resistance. These findings revise the current dogma of ubiquitous nucleotide biosynthesis in each proliferating cancer cell in a tumor and suggest that a programmed dTMP distribution maintains collective tumor growth. This mechanism could be exploited in cancer therapy.

cancer biology↗

bioRxiv2022

Mycobacterium tuberculosis requires the outer membrane lipid phthiocerol dimycocerosate for starvation-induced antibiotic tolerance

Tolerance of Mycobacterium tuberculosis to antibiotics contributes to the long duration of tuberculosis (TB) treatment and the emergence of drug-resistant strains. M. tuberculosis drug tolerance is induced by nutrient restriction, but the genetic determinants that promote antibiotic tolerance triggered by nutrient limitation have not been comprehensively identified. Here, we show that M. tuberculosis requires production of the outer membrane lipid phthiocerol dimycocerosate (PDIM) to tolerate antibiotics under nutrient-limited conditions. We developed an arrayed transposon (Tn) mutant library in M. tuberculosis Erdman and used orthogonal pooling and transposon sequencing (Tn-seq) to map the locations of individual mutants in the library. We screened a subset of the library (~1,000 mutants) by Tn-seq and identified 32 and 102 Tn mutants with altered tolerance to antibiotics in stationary phase and phosphate-starved conditions, respectively. Two mutants recovered from the arrayed library, ppgK::Tn and clpS::Tn, showed increased susceptibility to two different drug combinations in both nutrient-limited conditions, but their phenotypes were not complemented by the Tn-disrupted gene. Whole genome sequencing revealed single nucleotide polymorphisms in both the ppgK::Tn and clpS::Tn mutants that prevented PDIM production. Complementation of the clpS::Tn ppsD Q291* mutant with ppsD restored PDIM production and antibiotic tolerance, demonstrating that loss of PDIM sensitized M. tuberculosis to antibiotics. Our data suggest that drugs targeting production of PDIM, a critical M. tuberculosis virulence determinant, have the potential to enhance the efficacy of existing antibiotics, thereby shortening TB treatment and limiting development of drug resistance. IMPORTANCEMycobacterium tuberculosis causes 10 million cases of active TB disease and over 1 million deaths worldwide each year. TB treatment is complex, requiring at least 6 months of therapy with a combination of antibiotics. One factor that contributes to the length of TB treatment is M. tuberculosis phenotypic antibiotic tolerance, which allows the bacteria to survive prolonged drug exposure even in the absence of genetic mutations causing drug resistance. Here we report a genetic screen to identify M. tuberculosis genes that promote drug tolerance during nutrient starvation. Our study revealed the outer membrane lipid phthiocerol dimycocerosate (PDIM) as a key determinant of M. tuberculosis antibiotic tolerance triggered by nutrient starvation. Our study implicates PDIM synthesis as a potential target for development of new TB drugs that would sensitize M. tuberculosis to existing antibiotics to shorten TB treatment.

microbiology↗