Biology subjects

Merrild, C.

Publications and source records attributed to Merrild, C..

2 recordsLinked to original sources

bioRxiv2025

Sex-specific metabolic responses to modulation of the glucagon-FGF21 axis in female mice

Fibroblast growth factor 21 (FGF21) and glucagon are key regulators of energy homeostasis. However, male-biased preclinical studies overlook critical sex differences in metabolism, hindering our understanding of FGF21s role in glucagons effects on females and effective treatments for women with metabolic diseases. We investigated the physiological effects of FGF21 deficiency in female mice fed a chow or obesogenic diet. During chow-feeding, FGF21 deficiency had minimal impact on body weight, response to fasting, and voluntary exercise. However, Fgf21 knockouts (KO) fed the obesogenic diet exhibited increased adiposity compared to wild-type females. Long-acting glucagon analog treatment (LA-Gcg) reduced body weight in both genotypes but exacerbated glucose intolerance in female KOs. We also compared the effects of LA-Gcg and semaglutide, a glucagon-like peptide 1 analog, in diet-induced obese males and females. LA-Gcg treatment induced greater weight loss and reduced food intake in males, whereas semaglutide had similar effects across sexes. Furthermore, glucose tolerance was significantly worse in LA-Gcg- treated females compared to males. Concluding, FGF21 deficiency potentiates diet-induced obesity in female mice, and LA-Gcg elicits sex-specific effects on body weight and glucose tolerance, highlighting potential sexual dimorphisms to glucagon-based therapies and underscoring the importance of considering sex as a biological variable in metabolic research. HighlightsO_LIBiological sex fundamentally affects metabolism, yet this variable remains largely underexplored in metabolic research. C_LIO_LIThis study investigates how FGF21 deficiency affects metabolic responses in female mice, and compares the effects of a glucagon analog (LA-Gcg) and semaglutide in both sexes. C_LIO_LIFGF21 deficiency exacerbates diet-induced obesity in female mice. LA-Gcgs effects on body weight and glucose tolerance are modulated by FGF21 and sex-dependent, with females showing a blunted response to weight loss and worse glucose tolerance. C_LIO_LIOur findings highlight sex-specific differences in metabolic responses, emphasizing the need to consider sex as a key variable in the development of glucagon-based therapies. C_LI

physiology↗

bioRxiv2025

LRP2 expression in melanoma is associated with a transitory cell state, increased T cell infiltration, and is upregulated by IFNγ signaling

Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor expressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cells in the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. In previous work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma. However, the molecular drivers of LRP2 expression in melanoma and characteristics of LRP2-expressing melanoma have yet to be described. Here, we show that LRP2 expression is related to a transitory melanoma cell state defined by co-expression of melanocyte lineage and neural crest transcriptional programs. Further, we reveal that melanoma LRP2 expression is increased in T cell-inflamed tumors, and is directly upregulated through interferon-gamma signaling. Correlation of melanoma LRP2 expression with clinicopathological variables demonstrates that LRP2 expression is associated with low Breslow thickness and low clinical stage in primary melanomas. Taken together, the present study describes the characteristics of LRP2-expressing melanoma and reveals interferon gamma signaling as a novel strong positive regulator of LRP2 expression in melanoma. SignificanceMelanoma cells often acquire LRP2 expression but the drivers of LRP2 expression in this setting and characteristics of LRP2-expressing melanoma remain unclear. Here, we show that LRP2 expression is related to a transitory melanoma differentiation cell state. Further, LRP2 expression in melanoma correlates with a T cell-inflamed tumor microenvironment and LRP2 expression in melanoma cells can be directly increased by interferon-gamma. In addition, LRP2 expression is associated with less advanced histopathological characteristics of melanoma. These findings encourage future studies on LRP2 in settings with increased interferon signaling, in particular in melanoma metastases following immunotherapy.

cancer biology↗