Cre/lox generation of a novel whole-body Kiss1r KO mouse line recapitulates a hypogonadal, obese, and metabolically-impaired phenotype. (1st December 2019)

• Record Type: Journal Article
• Authors: Tolson, Kristen P.; Marooki, Nuha; Wolfe, Andrew; Smith, Jeremy T.; Kauffman, Alexander S.
• Is Part Of: Molecular and cellular endocrinology. Volume 498(2019)
• Publication Date: 2019-12-01
• Subjects: Kisspeptin -- Kiss1 -- Kiss1r -- GPR54 -- Adipose -- Fat -- Obesity -- Metabolism -- Energy expenditure; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2019.110559
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Kisspeptin and its receptor, Kiss1r, act centrally to stimulate reproduction. Recent evidence indicates that kisspeptin is also important for body weight and metabolism, as whole-body Kiss1r KO mice, developed with gene trap technology, display obesity and reduced metabolism. Kiss1r is expressed in brain and multiple peripheral tissues, but it is unknown which is responsible for the metabolic phenotype. Here, we sought to confirm that 1) the metabolic phenotype of the gene trap Kiss1r KOs is due to disruption of kisspeptin signaling and not off-target effects of viral mutagenesis, and 2) the Kiss1r flox line is suitable for creating conditional KOs to study the metabolic phenotype. We used Cre/lox technology ( Zp3 -Cre/ Kiss1r flox) to develop a new global Kiss1r KO (" Kiss1r gKO") to compare with the original gene trap KO phenotype. We confirmed that deleting exon 2 of Kiss1r from the entire body induces hypogonadism in both sexes. Moreover, global deletion of Kiss1r induced obesity in females, but not males, along with increased adiposity and impaired glucose tolerance, similar to the gene trap Kiss1r KOs. Likewise, Kiss1r gKO females had decreased VO2 and VCO2, likely underlying their obesity. These findings support that our previous results in gene trap Kiss1r KOs are due to disrupted kisspeptin signaling, and further highlight a role for Kiss1r signaling in energy expenditure and metabolism besides controlling reproduction. Moreover, given Kiss1r expression in multiple cell-types, our findings indicate that the Kiss1r flox line is viable for future investigations to isolate specific target cells of kisspeptin's metabolic effects. Highlights: We used Cre/lox technology to develop a novel global Kiss1r knock out ( Kiss1r gKO). Kiss1r gKO mice of both sexes are severely hypogonadal. Kiss1r gKO females, but not males, are obese with impaired glucose tolerance. Kiss1r gKO females show decreased VO2 and VCO2, likely underlying their obesity. No sex differences were identified in Kiss1 or Kiss1r expression in peripheral tissues.