Biology subjects

Henricsson, M.

Publications and source records attributed to Henricsson, M..

3 recordsLinked to original sources

bioRxiv2023

Adipocyte PI3K links adipostasis with insulin secretion through an adipoincretin effect

Insulin secretion is governed by insulin-PI3K signaling. Resolving the mechanism of this feedback is necessary to understand how insulin operates. Mice lacking the insulin receptor, or AKT1 and AKT2 in adipocytes, are severely lipoatrophic. Thus, the role of adipocyte insulin-PI3K signaling in the control of insulin secretion remains unknown. Using adipocyte- specific PI3K knockout mice (PI3KAdQ) and a panel of isoform-selective PI3K inhibitors, we have found that PI3K and PI3K{beta} activities are functionally redundant in adipocyte insulin signaling. PI3K{beta}-selective inhibitors had no effect on adipocyte AKT phosphorylation in control mice but blunted AKT phosphorylation specifically in adipocytes of PI3KAdQ mice, demonstrating adipocyte-selective inhibition of PI3K signaling. Adipocyte-selective PI3K inhibition increased serum FFA and potently induced insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect was dissociated from blood glucose and blood glucose counterregulatory response. The contribution of lipolysis, lipid, and amino acid metabolism, and selected adipokines to the adipoincretin effect has been investigated. We conclude that basal insulin secretion is chiefly controlled by adipocyte PI3K signaling through the adipoincretin effect. This phenomenon reveals an essential role for adipocyte insulin-PI3K signaling in linking the rates of adipose tissue lipolysis with baseline insulin secretion during fasting.

physiology↗

bioRxiv2023

TREM2 is downregulated by HSV1 in microglia and involved in antiviral defense in the brain

Immunological control of viral infection in the brain is essential for immediate protection, but also for long-term maintenance of brain integrity. As the primary resident immune cell of the brain, microglia protect against viral infections through key macrophage functions, including release of the antiviral type I interferons (IFN-I) and clearance of infected cells. Microglia express the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), which can bind viral DNA leading to signaling through stimulator of interferon genes (STING), and downstream immune activation. Here we report that herpes simplex virus (HSV) 1 infection of microglia leads to activation of IFN-I genes and pro-inflammatory cytokines. However, HSV1 also down-regulated expression of a subset of genes, including genes in the pathway engaged by the microglial receptor triggering receptor expressed on myeloid cells-2 (TREM2). Knockdown experiments revealed that TREM2 is important for viral activation of cGAS-STING signaling in microglia, induction of IFN-I, and phagocytosis of HSV1 infected neurons. Consequently, TREM2 depletion increased susceptibility to HSV1 infection in human microglia-neuron co-cultures and mice in vivo. Mechanistically, we show that TREM2 is essential for phosphorylation of STING, and downstream activation of the IFN-inducing transcription factor IRF3. We conclude that TREM2 is a novel component of the antiviral immune response in microglia, crucial for immediate host defense against HSV1 in the brain. Since both TREM2 loss-of-function mutations and HSV1 serological status are linked to development of Alzheime[r]s disease (AD), this work opens the question whether defects in TREM2 could predispose to impaired viral clearance and post-infection pathological neurological changes.

immunology↗

bioRxiv2021

Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using lipidomics and unbiased proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPAR{gamma} to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism achieve membrane homeostasis and adapt to a variable environment.

cell biology↗