Biology subjects

Amit, S.

Publications and source records attributed to Amit, S..

3 recordsLinked to original sources

bioRxiv2026

Myeloid Gi signaling acts as a weight-independent immunometabolic switch controlling systemic insulin sensitivity

Metabolic dysfunction does not necessarily correlate with adiposity. Metabolically healthy obese individuals and insulin-resistant lean individuals represent a fundamental paradox that implicates immune cell intrinsic mechanisms in the pathogenesis of type 2 diabetes. Here, we identify myeloid Gi signaling as a previously unrecognized determinant of whole-body glucose homeostasis. Single-cell transcriptomic analysis of adipose tissue macrophages from obese mice and humans reveals marked alteration in Gnai isoform, suggesting that myeloid Gi signaling is functionally engaged during metabolic disease. Using complementary myeloid-specific rodent models of Gi inhibition (pertussis toxin) and chemogenetic Gi activation (DREADD), we demonstrate that inhibition of Gi signaling improves glucose tolerance and enhances insulin sensitivity under both regular chow and high-fat diet conditions, independent of body weight and energy expenditure. Whereas acute Gi activation in lean mice modestly enhances glucose disposal, the same intervention during diet-induced obesity markedly impairs systemic glucose homeostasis, revealing context-dependent pathway function. Mechanistically, Gi inhibition amplifies macrophage cAMP-CREB signaling to drive IL-6 production, engaging STAT3- and AMPK-dependent pathways in adipose tissue and skeletal muscle to support insulin action. Conversely, Gi activation engages a previously uncharacterized G{beta}{gamma}-mTOR/AKT-JNK cascade, driving IL-1{beta} secretion that directly impairs insulin signaling in adipocytes and myotubes. Pharmacological IL-6 receptor blockade abolishes the metabolic benefits of Gi inhibition, whereas IL-1 receptor antagonism fully rescues Gi activation-induced metabolic dysfunction, establishing these cytokines as obligate downstream effectors. This signaling architecture is conserved in human macrophages, and ATAC-seq profiling reveals chromatin remodeling at cAMP-CREB and IL-6 regulatory pathway loci, consistent with the observed transcriptional reprogramming. Together, these findings establish myeloid Gi signaling as a weight-independent immunometabolic switch that couples opposing cytokine programs to systemic insulin sensitivity and identify this pathway as a therapeutic target in obesity-associated metabolic disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/713834v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@15e4576org.highwire.dtl.DTLVardef@224cd5org.highwire.dtl.DTLVardef@1e24888org.highwire.dtl.DTLVardef@1080bf3_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

physiology↗

bioRxiv2025

Acute activation of Gq-signaling in islet macrophages inhibits β-cell insulin secretion through AMPK-sphingolipid axis

Obesity-associated inflammation disrupts pancreatic {beta}-cell function, but the immune-derived signals that directly regulate insulin secretion remain incompletely defined. Here, we identify myeloid Gq signaling as a critical immunometabolic node that links macrophage activation to {beta}-cell dysfunction. For the first time, we employed a chemogenetic approach (DREADDs) to selectively and temporally activate Gq-coupled GPCR signaling in myeloid cells to examine its effect on islet function. Our findings reveal that acute Gq activation in islet-resident macrophages impaired glucose-stimulated insulin secretion, uncovering a previously unrecognized immune-endocrine axis. Conversely, myeloid-specific Gq deletion improves systemic glucose homeostasis, underscoring the physiological relevance of this pathway. Mechanistic analysis revealed that Gq activation in macrophages stimulates AMPK signaling and drives the secretion of sphingolipids. These lipids suppress insulin secretion and introduce a new mechanism for immune-islet communication, extending beyond traditional cytokine-based models. We further identify the lipid-sensing receptor GPR18 as an upstream activator of the Gq-AMPK pathway in macrophages. GPR18 stimulation recapitulated the Gq-dependent sphingolipid secretion and {beta}-cell inhibitory phenotype, which was abolished in myeloid Gq-deficient mice. Collectively, these findings establish a mechanistic framework whereby macrophage Gq signaling integrates lipid sensing and metabolic stress to modulate {beta}-cell function. This work reveals a previously unrecognized macrophage-{beta}-cell communication axis with therapeutic potential for restoring insulin secretion in metabolic diseases such as obesity and type 2 diabetes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/680858v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@790c4dorg.highwire.dtl.DTLVardef@116cceborg.highwire.dtl.DTLVardef@1e76631org.highwire.dtl.DTLVardef@e65770_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Monkeypox DNA correlates with virus infectivity in clinical samples

In light of the alarming global spread of Monkeypox and the lack of data regarding virus infectivity in clinical specimens, we examined virus infectivity and its correlation with PCR results, the currently available diagnostic tool. Due to the high risk of Monkeypox virus infection, only a limited number of approved BSL-3 laboratories employed with vaccinated staff, including ourselves, are capable of determining Monkeypox virus infectivity. We show strong correlation between viral DNA content and virus infectivity in clinical specimens. Moreover, we define a PCR threshold value which correspond to non-infectious virus, and suggest that our data can be translated into informed decision-making regarding risk assessment, protective measures and guidelines for Monkeypox patients.

microbiology↗