Tirzepatide preserves hematopoietic stem and progenitor cycling while remodeling inflammatory monocytes in obese mice

Tirzepatide may preserve hematopoietic stem cell function and reduce inflammatory monocytes compared to caloric restriction during weight loss, but the implications for human treatment require further investigation.

Summary and findings

This study measured the effects of tirzepatide on hematopoietic stem and progenitor cells (HSPCs) and inflammatory monocytes in obese mice. The findings indicated that tirzepatide preserved blood lineages and HSPC cycling compared to caloric restriction at equal weight loss. Not reported in abstract.

Abstract

Obesity expands myeloid progenitors, myelopoiesis and increases the production of monocytes. While weight loss (WL) alleviates aspects of this inflammatory dysregulation, it is not known whether GLP-1 receptor agonists or other traditional modalities of WL differentially modify hematopoietic stem/progenitor cells (HSPCs), hematopoiesis, or inflammatory cell production. To test this, we compared the hematopoietic compartment in lean, obese and weight-reduced mice from tirzepatide treatment and caloric restriction (CR) implemented to match the body weight in both groups. At equal WL, we found CR induced multilineage cytopenias, whereas tirzepatide preserved blood lineages while specifically reducing classical Ly6C hi CCR2 + monocytes. To define the mechanisms underlying these changes we performed single-cell mRNA sequencing of bone marrow HSPCs and mature mononuclear blood cells. CR-HSPCs suppressed gene sets associated with nutrient sensing, proliferation and oxidative phosphorylation (OXPHOS) and exhibited lower inferred cell cycle activity, whereas tirzepatide-HSPCs attenuated these changes. Unlike CR, we found that across progressively differentiated cells from HSPCs to mature blood monocytes, tirzepatide increasingly suppressed OXPHOS and simultaneously shifted the maturation spectrum away from classical monocytes. Following six weeks of tirzepatide withdrawal and weight regain, Ly6C hi CCR2 + monocytes rebounded to levels seen in obese mice. These findings suggest that tirzepatide uncouples WL from the broad hematopoietic suppression seen in CR by preserving progenitor activity but selectively remodeling inflammatory/classical monocytes. We demonstrate that WL modality differentially impacts hematopoietic adaptation and provide evidence that classical monocytes are an effector cell through which tirzepatide may dampen obesity-associated inflammation. Key Points At equivalent weight loss, calorie restriction causes cytopenias and suppresses HSPC cycling, while tirzepatide preserves these parameters Tirzepatide reduces inflammatory monocytes, shifts maturation, decreases OXPHOS genes, and monocytes rebound after drug withdrawal

Limitations

Not reported in abstract.

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