Studnitzer, B. | Search bioRxiv

bioRxiv2025

Dual Activation of MC3R and MC4R Drives Weight Loss and Reduces Food Intake in Obese Primates

Introductory ParagraphThe melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists prompted the investigation of whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation is key to unlocking the melanocortin system for the treatment of general obesity. To test this hypothesis, we designed and synthesized novel peptides to probe the distinct and combined roles of MC3R and MC4R in nonhuman primates (NHPs). We show that selectively agonizing MC3R modulates food intake in a state-dependent manner. Moreover, co-agonism of MC3R and MC4R results in more substantial metabolic effects than selective MC4R agonism, highlighting both a non-redundant and a cooperative role of MC3R. To leverage these discoveries, we developed 710GO, an orally-available MC3R/MC4R dual agonist peptide that induces significant weight loss in diet-induced obese (DIO) NHPs. Oral 710GO treatment demonstrates limited weight rebound, has additive effects in combination with GLP-1s, and exhibits a clean safety profile. These results reestablish the melanocortin system, specifically concerted MC3R/MC4R agonism, as a viable mechanism for next-generation obesity therapeutics.

neuroscience↗

bioRxiv2020

Identification, Characterization, and Targeting of a Rare and Temporal Dendritic Cell State that Facilitates Adaptive Immune Responses

The heterogeneity of innate immune cells facilitates efficient antigen presentation and immune activation in the presence of pathogens via cooperativity of various cell subsets and cell states but also obscures the contribution of individual antigen presenting cells (APCs) to overall immune response.1 It has been hypothesized that a small number of APCs, which are more sensitive to the initial pathogen stimulus, are responsible for coordinating neighboring APCs in an effort to share the metabolic strain associated with heightened pathogen sensitivity.2 In this study, we have identified a temporally-controlled state of dendritic cells (DCs) that demonstrate greater sensitivity to toll-like-receptor (TLR) agonists and secrete the majority of paracrine activating cytokines (TNF, IL-6...ect). We were able to isolate this distinct population of DCs preferentially phagocytosed the majority of fluorescently labeled, TLR agonist conjugated microparticles (MPs).3 We call this population First Responder cells (FRs) due to their ability to first uptake the MPs and activate neighboring APCs via paracrine signaling. We show that FRs exist in this state for <3 hours, cycle through this state on a <24-hour timescale and show a distinct mRNA profile. Furthermore, FRs are necessary for generation of adaptive responses both in vitro and in vivo. We also show that we can improve both IgG titers and CD8 responses in vivo by targeting two highly upregulated receptors on FR cells, DAP12 and PRG2. Given the significance of FR involvement in APC activation, this study has broad immunological value because it offers a critical first evaluation of a new APC cell state but also has important translational value for improving vaccine efficacy via FR targeting.

immunology↗