MON-621 - Autonomic Regulation of Bone Marrow Adiposity and Hematopoiesis in Type 2 Diabetes

Chronic inflammation is one of the hallmarks of type 2 diabetes (T2D) and involves dysfunction of hematopoietic stem cells (HSCs) in the bone marrow (BM), where a reservoir of adipocytes expands in T2D and may bias HSCs towards inflammatory lineages. However, the mechanisms linking metabolic cues in T2D to changes in BM adiposity and HSCs remain poorly understood. Emerging evidence implicates the autonomic nervous system (ANS) as a key mediator of metabolic and inflammatory homeostasis. We recently reported that mice deficient in PTEN, a negative regulator of PI3K/AKT signalling, in paired-like homeobox 2B (Phox2B) neurons exhibit enhanced vagus nerve function and sympathetic innervation of white adipose tissue, protecting against high fat diet (HFD)-induced obesity, insulin resistance, and systemic inflammation. Combined with evidence of decreased sympathetic bone innervation in T2D, these findings suggest that the ANS may regulate BM adiposity and hematopoiesis.

To investigate the effect of enhanced PI3K signalling in Phox2B neurons on BM adiposity, Phox2Bcre+Ptenfl/fl knockout (P-Pten KO) mice and Phox2Bcre+Ptenwt/wt (P-Pten WT) littermates began a 60% HFD at 6 weeks of age for 3 or 6 months, with a parallel cohort continuing a normal chow diet (NCD) (4% fat content). High-resolution micro-computed tomography (µ-CT) of osmium tetroxide (OsO4)-stained samples and Oil Red O (ORO) staining were used to quantify adiposity in the tibiae. To investigate changes in hematopoiesis, HSC lineages, including multipotent progenitors (MPPs), myeloid and lymphoid progenitors, and mature BM cells were assessed by flow cytometry. Experiments were performed on males and females and analyzed separately.

In basal conditions, µ-CT imaging revealed a predominance of adiposity in distal tibiae with similar degrees in P-Pten WT and KO mice on NCD. However, after 6 months on HFD, increases in BM adiposity occurred primarily in the proximal tibiae of P-Pten WT mice. This expansion was attenuated in P-Pten KO mice, shown by µ-CT (OSO4+%, WT vs KO, n=5 mean±SD: 14.66±7.91 vs 2.032±2.22, p=0.0035) and by ORO staining in the proximal (ORO+%, WT vs KO, n=7 mean±SD: 28.53±7.55 vs 7.67±7.47, p=0.0008) and distal tibia (ORO+ %, WT vs KO, n=7 mean±SD: 60.35±6.49 vs 42.02±8.66, p=0.0018). HSCs, MPPs, and mature BM cell populations were comparable between female 18-week-old P-Pten WT and KO mice on NCD. However, after 3 months on HFD, P-Pten WT mice showed an expanded population of typically quiescent long term HSCs (LT-HSCs) that was significantly attenuated in P-Pten KO mice (MPP%, WT vs KO, n=7 mean±SD: 29.60±2.61 vs 21.29±5.51, p=0.0006). Similar results were seen in males.

Together, we show that Pten deletion in Phox2B neurons protects against HFD-driven increases in BM adiposity and LT-HSCs, identifying PI3K signalling in ANS neurons as a potential key regulator of hematopoiesis determining inflammatory status in T2D.

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