Biology subjects

Sarker, G.

Publications and source records attributed to Sarker, G..

3 recordsLinked to original sources

bioRxiv2024

The perineurium integrates leptin with its sympathetic outflow to protect against obesity

The regulatory mechanism of leptins afferent action in the brain, constituting a negative feedback loop, is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the relative strengths of the afferent and efferent arms remains ambiguous. Using single-cell RNA sequencing on murine sympathetic ganglia, we identified the unique expression of both the leptin receptor (LepR) and the beta 2 adrenergic receptor (Adrb2) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues. We show that LepR+ Sympathetic Perineurial Cells (SPCs) are molecularly similar to endothelial cells and that conditional knockout of Adrb2 in LepR+ SPCs predisposes mice to obesity without affecting food intake. Notably, we found that hyperleptinemia associated with obesity causes apoptosis in SPCs, leading to a significant erosion of the perineurial barrier and concomitant adipose sympathetic neuropathy. We further show that this deleterious effect can be reversed by sympathomimetic beta 2 adrenergic receptor agonism. These results have relevance to human obesity, as we observed a synergistic effect of highly common polymorphisms of LEPR and ADRB2 on the risk of increased BMI in a large European population. We propose that SPCs are the nexus of leptin action by integrating the afferent and efferent arms of the neuroendocrine loop to influence its setpoint.

neuroscience↗

bioRxiv2024

Sympathetic neuron-derived NPY protects from obesity by sustaining the mural progenitors of thermogenic adipocytes.

Neuropeptide Y (NPY) is secreted by sympathetic nerves1,2, but its direct impact on thermogenic adipocytes is unknown. Here we uncover the mechanism by which peripheral NPY protects from obesity. Our imaging of cleared murine brown and white adipose tissue (BAT and WAT) established that NPY+ sympathetic axons are only a minority that mostly maps to the peri-vasculature; our analysis of single-cell RNA-sequencing datasets identifies mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains mural cells, which are known to be a source of beige cells in both BAT and WAT3-5 and that NPY facilitates the differentiation to thermogenic adipocytes. We found that diet-induced-obesity leads to neuropathy of NPY+ axons and concomitant depletion of the mural cell pool of beige fat progenitors. This defect is replicated in conditional knockout (cKO) mice with NPY specifically abrogated from sympathetic neurons. These cKO mice have whitened BAT with reduced thermogenic ability and lower energy expenditure even before the onset of obesity; they develop adult-onset obesity on a regular chow diet and are more susceptible to diet induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by the sympathetic nerves has the opposite effect on body weight homeostasis by sustaining the proliferation of the mural cell progenitors of thermogenic adipocytes.

physiology↗

bioRxiv2023

Immunomodulatory Leptin Receptor+ Sympathetic Perineurial Cells Protect Against Obesity by Facilitating Neuroendocrine-Mediated Brown Adipose Tissue Thermogenesis

Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor (LepR)-expressing barrier cells which ensheath sympathetic axon bundles in adipose tissues. These LepR-expressing Sympathetic Perineurial Cells (SPCs) produce IL33, a factor for maintenance and recruitment of regulatory T cell (Treg) and eosinophils in AT. Brown adipose tissues (BAT) of mice lacking IL33 in SPCs (SPCIL33cKO) have fewer Treg and eosinophils, resulting in increased BAT inflammation. SPCIL33cKO mice are more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCIL33cKO mice have impaired adaptive thermogenesis, and are unresponsive to leptin-induced rescue of metabolic adaptation. We, therefore, identify LepR-expressing SPCs as a source of IL33 which orchestrate an anti-inflammatory environment in BAT, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+ IL33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/539963v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@195fa69org.highwire.dtl.DTLVardef@16b2e5eorg.highwire.dtl.DTLVardef@1b12b62org.highwire.dtl.DTLVardef@973c1b_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- Sympathetic Perineurial Cells (SPCs) co-express LepR+ and IL33 - SPC-derived IL33 prevents BAT inflammation via Treg and eosinophil recruitment - Obesity is worsened in high fat diet-fed SPCIL33cKO mice, despite normal food intake - Adaptive thermogenesis is impaired in SPCIL33cKO mice - Rescue of metabolic adaptation to fasting by leptin is impaired in SPCIL33cKO mice - SPCs link leptin to immunometabolic regulation of body weight homeostasis

physiology↗