Biology subjects

Lu, W. W.

Publications and source records attributed to Lu, W. W..

3 recordsLinked to original sources

bioRxiv2023

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

Ectopic bone marrow adipocytes (BMAds) accumulation occurring under diverse pathophysiological conditions leads to bone deterioration. Estrogen-related receptor (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency rescues osteogenesis and vascular formation in adipocyte-rich bone marrow due to estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); and positively modulates Leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased LEPTIN secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/552932v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1132da3org.highwire.dtl.DTLVardef@19342aorg.highwire.dtl.DTLVardef@afe8d7org.highwire.dtl.DTLVardef@dfb1f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2020

Central Neural Regulation of Parathyroid Hormone

Parathyroid hormone (PTH) is one of the most important hormones responsible for bone turnover and calcium homeostasis. In mammals, PTH is secreted through the parathyroid glands, unlike in fishes, which are secreted through central nervous system. Studies indicated that a variety of peripheral nerve regulates serum PTH level, however, the mechanism underlying central neural regulation of PTH in mammals remains largely unknown. With an approach including neural-specific retrograde tracing, PTH-Biotin binding assay, and cFos staining, we identified the subfornical organ (SFO) and the paraventricular nucleus (PVN) as two important brain nuclei that responded to serum PTH and calcium changes. Using chemogenetics, we found that serum PTH was suppressed by stimulation of GABAergic neurons in SFO followed by a decrease in trabecular bone mass. Conversely, stimulation of glutamatergic neurons in SFO promoted serum PTH and bone mass. Moreover, we found that the majority of neurons expressing parathyroid hormone 1 receptor (PTH1R) were GABAergic neurons and the majority of neurons expressing parathyroid hormone 2 receptor (PTH2R) were glutamatergic neurons. The paraventricular nucleus (PVN) is downstream of the SFO, and chemogenetic activation of glutamatergic neurons in PVN induced an increase in serum PTH. In summary, our study demonstrates for the first time that distinct neuronal subtypes in the SFO are responsible for bidirectional regulation of serum PTH and bone metabolism, which is mediated through the PVN and the peripheral nervous system. These findings reveal important central neural nodes and will advance our understanding of the central neural regulation of PTH at the molecular, cellular and circuit level.

neuroscience↗

bioRxiv2019

Identification of a Central Neural Circuit that Regulates Anxiety-induced Bone Loss

The homeostasis of bone metabolism is finely regulated by the central nervous system and recent studies have suggested that mood disorders, such as anxiety, are closely related to bone metabolic abnormalities; however, our understanding of central neural circuits regulating bone metabolism is still largely limited. In this study, we first demonstrate that confined isolation of human participants under normal gravity resulted in decreased bone density and elevated anxiety levels. We then used an established mouse model to dissect the neural circuitry regulating anxiety-induced bone loss. Combining electrophysiological, optogenetic and chemogenetic approaches, we demonstrate that GABAergic neural circuitry in ventromedial hypothalamus (VMH) modulates anxiety-induced bone loss; importantly, the GABAergic input in VMHdm arose from a specific group of somatostatin neurons in the bed nucleus of the stria terminalis (BNST), which is both indispensable for anxiety-induced bone loss and able to trigger bone loss in the absence of stressors. VGLUT2 neurons in Nucleus tractus solitaries (NTS) and peripheral sympathetic system were employed by this BNST-VMH neural circuit to regulate anxiety-induced bone loss. Overall, we uncovered new GABAergic neural circuitry from the forebrain to hypothalamus, used in the regulation of anxiety-induced bone loss, and revealed a population of somatostatin neurons in BNST not previously implicated in bone mass regulation. These findings thus identify the underlying central neural mechanism of psychiatric disorders, such as anxiety, that influences bone metabolism at the circuit level.\n\nOne Sentence SummaryIdentification of a new GABAergic neural circuit from forebrain to hypothalamus used for regulation of anxiety-induced bone loss.

neuroscience↗