Biology subjects

Koneru, J.

Publications and source records attributed to Koneru, J..

3 recordsLinked to original sources

bioRxiv2023

ATF4 Expression in Thermogenic Adipocytes is Required for Cold-Induced Thermogenesis in Mice via FGF21-Independent Mechanisms

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially via upregulation of FGF21. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue (WAT). Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis by activating amino acid metabolism in BAT in a FGF21-independent manner. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/531964v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1d2c3fdorg.highwire.dtl.DTLVardef@414f5forg.highwire.dtl.DTLVardef@1c1fa9eorg.highwire.dtl.DTLVardef@2cc815_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

GDF15 Is Required for Cold-Induced Thermogenesis and Contributes to Improve Systemic Metabolic Health Following Loss of OPA1 in Brown Adipocytes

Previously we showed that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates at baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice [1]. To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15) in BAT. To determine if ATF4 induction was mediated by the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and to evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice lacking both OPA1 and PERK in BAT had preserved induction of ATF4. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to diet-induced obesity and abrogated the improvements in glucose tolerance. Furthermore, GDF15 mediated cold-induced thermogenesis, likely via sympathetic activation of iWAT. Taken together, our data indicate that PERK is dispensable for ATF4 induction, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice.

physiology↗

bioRxiv2021

Molecular View of Biomimetic Peptide in Action with Membrane

Amphiphilic {beta}-peptides, which are synthetically designed short-chain helical foldamer of {beta}-amino acids, are established potent biomimetic alternatives of natural antimicrobial peptides. An intriguing question is: how does the distinct molecular architecture of these short-chain and rigid synthetic peptides translates to its potent membrane disruption ability? Here, we address this question via a combination of all atom and coarse-grained molecular dynamics simulations of the interaction of mixed phospholipid bilayer with an antimicrobial 10-residue globally amphiphilic helical {beta}-peptide at wide range of concentrations. The simulation demonstrates that multiple copies of this synthetic peptide, initially placed in aqueous solution, readily self-assemble and adsorb at membrane interface. Subsequently, beyond a threshold peptide-to-lipid ratio, the surface-adsorbed oligomeric aggregate moves inside the membrane and spontaneously forms stable water-filled transmembrane pore via a cooperative mechanism. The defects induced by these pores lead to the dislocation of interfacial lipid head groups, membrane thinning and substantial water leakage inside the hydrophobic core of the membrane. A molecular analysis reveals that, despite having a short architecture, these synthetic peptides, once inside the membrane, would stretch themselves towards the distal leaflet in favour of potential contact with polar head groups and interfacial water layer. The pore formed in coarse-grained simulation was found to be resilient upon structural refinement. Interestingly, the pore-inducing ability was found to be elusive in a non-globally amphiphilic sequence isomer of the same {beta}-peptide, indicating strong sequence dependence. Taken together, this work put forward key perspectives of membrane-activity of minimally designed synthetic biomimetic oligomers relative to the natural antimicrobial peptides. STATEMENT OF SIGNIFICANCEThe development of bacterial resistance to conventional antibiotics is a major concern towards public health. Antimicrobial peptides, which provide a natural defence against a large range of pathogens, including bacteria and fungi, are emerging as a sustainable substitute of antibiotics. However, serious issues with the naturally occurring antimicrobial peptides which have prevented their wide-spread appreciations are their susceptibility to degradation and lack of specificity for microbial targets. In this regard, synthetic biomimetic peptides are coming up as a viable alternative. In this work we provide clarity on how these synthetic antimicrobial peptides, which often involves distinctly short architecture, acts on the membrane. We show that despite its short architecture, a 10-residue biomimetic peptide, {beta}-peptide, can spontaneously form stable membrane-spanning pore and induce water-leakage inside the membrane.

biophysics↗