---
title: "Tirzepatide preserves HSPC cycling and reduces inflammatory Ly6Chi CCR2+ monocytes during weight l"
id: "biorxiv-2-tirzepatide-preserves-hematopoietic-stem-and-progenitor-cycling-while"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-2-tirzepatide-preserves-hematopoietic-stem-and-progenitor-cycling-while"
content_type: "clinical_feed_article"
specialty: "Hematology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.01.748392v1?rss=1"
published_at: "2026-09-04T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Tirzepatide preserves HSPC cycling and reduces inflammatory Ly6Chi CCR2+ monocytes during weight l
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-2-tirzepatide-preserves-hematopoietic-stem-and-progenitor-cycling-while
- **Specialty:** [Hematology](https://medichelpline.com/clinical-feed/hematology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.01.748392v1?rss=1)
- **Published At:** 2026-09-04T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Obesity drives expansion of **myeloid progenitors**, increased **myelopoiesis**, and elevated monocyte production in mice. Weight loss can reduce this inflammatory state, but effects vary by weight-loss modality. - This study compared lean mice, obese mice, and weight-reduced (WL) mice achieving matched body weight loss via either **tirzepatide** treatment or caloric restriction (CR). - Caloric restriction produced broad multilineage **cytopenias**, indicating generalized suppression of hematopoiesis after WL by CR. - Tirzepatide-treated, weight-matched mice retained peripheral blood lineages while selectively lowering classical **Ly6Chi CCR2+ monocytes** rather than causing broad cytopenias. - Single-cell mRNA sequencing of bone marrow hematopoietic stem/progenitor cells (**HSPCs**) and mature blood mononuclear cells revealed distinct transcriptional programs between CR and tirzepatide groups. - CR-HSPCs showed suppression of gene sets linked to **nutrient sensing**, **proliferation**, and **oxidative phosphorylation (OXPHOS)**, with lower inferred cell-cycle activity compared with obese or lean controls. - Tirzepatide-HSPCs partially attenuated these CR-associated suppressive changes, preserving progenitor cycling and activity. - Across progressive differentiation from HSPCs to mature monocytes, tirzepatide increasingly suppressed **OXPHOS** gene programs and shifted the maturation trajectory away from classical monocytes. - After six weeks off tirzepatide with weight regain, Ly6Chi CCR2+ monocyte numbers returned to levels observed in obese mice, indicating the effect on classical monocytes is reversible and linked to ongoing treatment or weight status. - Authors conclude tirzepatide can uncouple weight loss from the broad hematopoietic suppression seen with CR by preserving progenitor activity while selectively remodeling inflammatory/classical monocytes, implicating classical monocytes as an effector cell population mediating reduced obesity-associated inflammation. - Competing interest note: JR reported multiple industry affiliations; other authors reported no competing interests. Funding sources were declared from NIH and a foundation in the source text.
## Clinical Analysis & Structured Key Points
Tirzepatide preserves hematopoietic stem and progenitor cycling while remodeling inflammatory monocytes in obese mice | bioRxiv Skip to main content New Results Tirzepatide preserves hematopoietic stem and progenitor cycling while remodeling inflammatory monocytes in obese mice View ORCID Profile Nathan M. Krah , View ORCID Profile Elena Gonzalez-Alvarado , View ORCID Profile Amog P. Urs , View ORCID Profile Chinmayee Goda , View ORCID Profile Yaphet Bustos , James E. Marvin , View ORCID Profile Bradley D. Weaver , Spencer Gygi , View ORCID Profile Ashish Toshniwal , Dennis Towne , Alvaro J. Narbona-Perez , View ORCID Profile Katarina E. Heyden , View ORCID Profile Juan A. Cantres-Velez , View ORCID Profile Corey N. Cunningham , View ORCID Profile Sankalp Arora , Ramiro Garzon , View ORCID Profile Jared Rutter , View ORCID Profile Adrienne M. Dorrance , View ORCID Profile Amandine Chaix doi: https://doi.org/10.64898/2026.09.01.748392 Nathan M. Krah 1 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nathan M. Krah For correspondence: nathan.krah{at}hci.utah.edu Elena Gonzalez-Alvarado 2 Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elena Gonzalez-Alvarado Amog P. Urs 1 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Amog P. Urs Chinmayee Goda 1 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Chinmayee Goda Yaphet Bustos 1 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Yaphet Bustos James E. Marvin 3 Health Science Center Flow Cytometry Core Facility, University of Utah, Salt Lake City, UT, USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bradley D. Weaver 4 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Bradley D. Weaver Spencer Gygi 5 Department of Biochemistry, University of Utah Medical School, Salt Lake City, UT 84112 USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ashish Toshniwal 5 Department of Biochemistry, University of Utah Medical School, Salt Lake City, UT 84112 USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ashish Toshniwal Dennis Towne 6 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alvaro J. Narbona-Perez 7 Department of Biochemistry, University of Utah Medical School, Salt Lake City, UT 84112 USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Katarina E. Heyden 7 Department of Biochemistry, University of Utah Medical School, Salt Lake City, UT 84112 USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Katarina E. Heyden Juan A. Cantres-Velez 7 Department of Biochemistry, University of Utah Medical School, Salt Lake City, UT 84112 USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Juan A. Cantres-Velez Corey N. Cunningham 7 Department of Biochemistry, University of Utah Medical School, Salt Lake City, UT 84112 USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Corey N. Cunningham Sankalp Arora 6 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sankalp Arora Ramiro Garzon 6 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jared Rutter 8 Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112 USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jared Rutter Adrienne M. Dorrance 6 Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Adrienne M. Dorrance Amandine Chaix 9 Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Amandine Chaix Abstract Info/History Metrics Supplementary material Preview PDF 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 Ly6Chi 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, Ly6Chi 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. Competing Interest Statement JR: No COI related to the current work. Founder, SAB/BOD member, Consultant or Research Funding from: Vettore Biosciences, RiverVest Venture Partners, Centaurus Therapeutics, Pfizer, Calico Laboratories, Atavistik Bio, Reina Bio All other authors: no competing interests to disclose. Funder Information Declared National Institutes of Health, https://ror.org/01cwqze88 , P30CA042014 , F32HL177926 , UH2CA286584 , P30DK020579 Joe W. and Dorothy Dorsett Brown Foundation, https://ror.org/043291659 , Young Investigator Award to NMK Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 04, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Dorrance , Amandine Chaix bioRxiv 2026.09.01.748392; doi: https://doi.org/10.64898/2026.09.01.748392 Share This Article: Copy Citation Tools Tirzepatide preserves hematopoietic stem and progenitor cycling while remodeling inflammatory monocytes in obese mice Nathan M. Krah , Elena Gonzalez-Alvarado , Amog P. Urs , Chinmayee Goda , Yaphet Bustos , James E. Marvin , Bradley D. Weaver , Spencer Gygi , Ashish Toshniwal , Dennis Towne , Alvaro J. Narbona-Perez , Katarina E. Heyden , Juan A. Cantres-Velez , Corey N. Cunningham , Sankalp Arora , Ramiro Garzon , Jared Rutter , Adrienne M. 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