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Article: Cre/lox generation of a novel whole-body Kiss1r KO mouse line recapitulates a hypogonadal, obese, and metabolically-impaired phenotype

Tolson, Kristen P / Marooki, Nuha / Wolfe, Andrew / Smith, Jeremy T / Kauffman, Alexander S

Molecular and cellular endocrinology. 2019 Aug. 19,

2019

Abstract: Kisspeptin and its receptor, Kiss1r, act in 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 ... ...

Abstract	Kisspeptin and its receptor, Kiss1r, act in 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.
Keywords	adiposity ; brain ; energy expenditure ; exons ; females ; glucose tolerance ; kisspeptin ; males ; mice ; mutagenesis ; obesity ; phenotype ; reproduction ; tissues
Language	English
Dates of publication	2019-0819
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2019.110559
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Cre/lox generation of a novel whole-body Kiss1r KO mouse line recapitulates a hypogonadal, obese, and metabolically-impaired phenotype.

Tolson, Kristen P / Marooki, Nuha / Wolfe, Andrew / Smith, Jeremy T / Kauffman, Alexander S

Molecular and cellular endocrinology

2019 Volume 498, Page(s) 110559

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 ... ...

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 VO
MeSH term(s)	Adiposity ; Animals ; Body Weight ; Energy Metabolism ; Female ; Glucose Intolerance/etiology ; Glucose Intolerance/metabolism ; Glucose Intolerance/pathology ; Hypogonadism/etiology ; Hypogonadism/metabolism ; Hypogonadism/pathology ; Integrases/genetics ; Integrases/metabolism ; Male ; Metabolic Diseases/etiology ; Metabolic Diseases/metabolism ; Metabolic Diseases/pathology ; Mice ; Mice, Knockout ; Obesity/etiology ; Obesity/metabolism ; Obesity/pathology ; Phenotype ; Receptors, Kisspeptin-1/physiology ; Reproduction ; Signal Transduction
Chemical Substances	Kiss1r protein, mouse ; Receptors, Kisspeptin-1 ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2019-08-20
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2019.110559
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Article ; Online: The Changes They are A-Timed: Metabolism, Endogenous Clocks, and the Timing of Puberty.

Tolson, Kristen P / Chappell, Patrick E

Frontiers in endocrinology

2012 Volume 3, Page(s) 45

Abstract: Childhood obesity has increased dramatically over the last several decades, particularly in industrialized countries, often accompanied by acceleration of pubertal progression and associated reproductive abnormalities (Biro et al., 2006; Rosenfield et al. ...

Abstract	Childhood obesity has increased dramatically over the last several decades, particularly in industrialized countries, often accompanied by acceleration of pubertal progression and associated reproductive abnormalities (Biro et al., 2006; Rosenfield et al., 2009). The timing of pubertal initiation and progression in mammals is likely influenced by nutritional and metabolic state, leading to the hypothesis that deviations from normal metabolic rate, such as those seen in obesity, may contribute to observed alterations in the rate of pubertal progression. While several recent reviews have addressed the effects of metabolic disorders on reproductive function in general, this review will explore previous and current models of pubertal timing, outlining a potential role of endogenous timing mechanisms such as cellular circadian clocks in the initiation of puberty, and how these clocks might be altered by metabolic factors. Additionally, we will examine recently elucidated neuroendocrine regulators of pubertal progression such as kisspeptin, explore models detailing how the mammalian reproductive axis is silenced during the juvenile period and reactivated at appropriate developmental times, and emphasize how metabolic dysfunction such as childhood obesity may alter timing cues that advance or delay pubertal progression, resulting in diminished reproductive capacity.
Language	English
Publishing date	2012-03-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592084-4
ISSN	1664-2392 ; 1664-2392
ISSN (online)	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2012.00045
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Article: The development of kisspeptin circuits in the Mammalian brain.

Semaan, Sheila J / Tolson, Kristen P / Kauffman, Alexander S

Advances in experimental medicine and biology

2013 Volume 784, Page(s) 221–252

Abstract: The neuropeptide kisspeptin, encoded by the Kiss1 gene, is required for mammalian puberty and fertility. Examining the development of the kisspeptin system contributes to our understanding of pubertal progression and adult reproduction and sheds light on ...

Abstract	The neuropeptide kisspeptin, encoded by the Kiss1 gene, is required for mammalian puberty and fertility. Examining the development of the kisspeptin system contributes to our understanding of pubertal progression and adult reproduction and sheds light on possible mechanisms underlying the development of reproductive disorders, such as precocious puberty or hypogonadotropic hypogonadism. Recent work, primarily in rodent models, has begun to study the development of kisspeptin neurons and their regulation by sex steroids and other factors at early life stages. In the brain, kisspeptin is predominantly expressed in two areas of the hypothalamus, the anteroventral periventricular nucleus and neighboring periventricular nucleus (pre-optic area in some species) and the arcuate nucleus. Kisspeptin neurons in these two hypothalamic regions are differentially regulated by testosterone and estradiol, both in development and in adulthood, and also display differences in their degree of sexual dimorphism. In this chapter, we discuss what is currently known and not known about the ontogeny, maturation, and sexual differentiation of kisspeptin neurons, as well as their regulation by sex steroids and other factors during development.
MeSH term(s)	Adult ; Animals ; Anterior Thalamic Nuclei/growth & development ; Anterior Thalamic Nuclei/metabolism ; Arcuate Nucleus of Hypothalamus/growth & development ; Arcuate Nucleus of Hypothalamus/metabolism ; Estradiol/metabolism ; Female ; Gene Expression Regulation/physiology ; Humans ; Hypogonadism/metabolism ; Kisspeptins/metabolism ; Male ; Puberty/physiology ; Puberty, Precocious/metabolism ; Reproduction/physiology ; Sex Characteristics ; Testosterone/metabolism
Chemical Substances	KISS1 protein, human ; Kisspeptins ; Testosterone (3XMK78S47O) ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2013-04-03
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4614-6199-9_11
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Article ; Online: Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice.

Tolson, Kristen P / Garcia, Christian / Delgado, Iris / Marooki, Nuha / Kauffman, Alexander S

Endocrinology

2016 Volume 157, Issue 11, Page(s) 4192–4199

Abstract: Kisspeptin regulates reproduction via signaling through the receptor, Kiss1r, in GnRH neurons. However, both kisspeptin and Kiss1r are produced in several peripheral tissues, and recent studies have highlighted a role for kisspeptin signaling in ... ...

Abstract	Kisspeptin regulates reproduction via signaling through the receptor, Kiss1r, in GnRH neurons. However, both kisspeptin and Kiss1r are produced in several peripheral tissues, and recent studies have highlighted a role for kisspeptin signaling in metabolism and glucose homeostasis. We recently reported that Kiss1r knockout (KO) mice display a sexually dimorphic metabolic phenotype, with KO females displaying obesity, impaired metabolism, and glucose intolerance at 4-5 months of age. However, it remains unclear when this metabolic phenotype first emerges in development, or which aspects of the pleiotropic phenotype underlie the metabolic defects and which are secondary to the obesity. Here, we studied Kiss1r KO females at different ages, including several weeks before the emergence of body weight (BW) differences and later when obesity is present. We determined that at young adult ages (6 wk old), KO females already exhibit altered adiposity, leptin levels, metabolism, and energy expenditure, despite having normal BWs at this time. In contrast, food intake, water intake, and glucose tolerance are normal at young ages and only show impairments at older adult ages, suggesting that these impairments may be secondary to earlier alterations in metabolism and adiposity. We also demonstrate that, in addition to BW, all other facets of the adult metabolic phenotype persist even when gonadal sex steroids are similar between genotypes. Collectively, these data highlight the developmental emergence of a metabolic phenotype induced by disrupted kisspeptin signaling and reveal that multiple, but not all, aspects of this phenotype are already disrupted before detectable changes in BW.
MeSH term(s)	Adiposity/physiology ; Animals ; Body Composition/genetics ; Body Composition/physiology ; Body Weight/physiology ; Eating/physiology ; Energy Metabolism/genetics ; Energy Metabolism/physiology ; Female ; Glucose Intolerance/genetics ; Glucose Intolerance/physiopathology ; Glucose Tolerance Test ; Leptin/blood ; Male ; Mice ; Mice, Knockout ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Kisspeptin-1 ; Signal Transduction
Chemical Substances	Kiss1r protein, mouse ; Leptin ; Receptors, G-Protein-Coupled ; Receptors, Kisspeptin-1
Language	English
Publishing date	2016-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2016-1501
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Article ; Online: Unaltered Hypothalamic Metabolic Gene Expression in Kiss1r Knockout Mice Despite Obesity and Reduced Energy Expenditure.

De Bond, Julie-Ann P / Tolson, Kristen P / Nasamran, Chanond / Kauffman, Alexander S / Smith, Jeremy T

Journal of neuroendocrinology

2016 Volume 28, Issue 10

Abstract: Kisspeptin controls reproduction by stimulating gonadotrophin-releasing hormone neurones via its receptor Kiss1r. Kiss1r is also expressed other brain areas and in peripheral tissues, suggesting additional nonreproductive roles. We recently determined ... ...

Abstract	Kisspeptin controls reproduction by stimulating gonadotrophin-releasing hormone neurones via its receptor Kiss1r. Kiss1r is also expressed other brain areas and in peripheral tissues, suggesting additional nonreproductive roles. We recently determined that Kiss1r knockout (KO) mice develop an obese and diabetic phenotype. In the present study, we investigated whether Kiss1r KOs develop this metabolic phenotype as a result of alterations in the expression of metabolic genes involved in the appetite regulating system of the hypothalamus, including neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc), as well as leptin receptor (Lepr), ghrelin receptor (Ghsr), and melanocortin receptors 3 and 4 (Mc3r, Mc4r). Body weights, leptin levels and hypothalamic gene expression were measured in both gonad-intact and gonadectomised (GNX) mice at 8 and 20 weeks of age that had received either normal chow or a high-fat diet. We detected significant increases in Pomc expression in gonad-intact Kiss1r KO mice at 8 and 20 weeks, although there were no alterations in the other metabolic-related genes. However, the Pomc increases appeared to reflect genotype differences in circulating sex steroids, because GNX wild-type and Kiss1r KO mice exhibited similar Pomc levels, along with similar Npy levels. The altered Pomc gene expression in gonad-intact Kiss1r KO mice is consistent with previous reports of reduced food intake in these mice and may serve to increase the anorexigenic drive, perhaps compensating for the obese state. However, the surprising overall lack of changes in any of the hypothalamic metabolic genes in GNX KO mice suggests that the aetiology of obesity in the absence of kisspeptin signalling may reflect peripheral rather than central metabolic impairments.
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	1007517-3
ISSN	1365-2826 ; 0953-8194
ISSN (online)	1365-2826
ISSN	0953-8194
DOI	10.1111/jne.12430
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Zs.A 2634: Show issues

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Article ; Online: Developmental GnRH signaling is not required for sexual differentiation of kisspeptin neurons but is needed for maximal Kiss1 gene expression in adult females.

Kim, Joshua / Tolson, Kristen P / Dhamija, Sangeeta / Kauffman, Alexander S

Endocrinology

2013 Volume 154, Issue 9, Page(s) 3273–3283

Abstract: Kisspeptin, encoded by Kiss1, stimulates reproduction. In rodents, one Kiss1 population resides in the hypothalamic anterior ventral periventricular nucleus and neighboring rostral periventricular nucleus (AVPV/PeN). AVPV/PeN Kiss1 neurons are sexually ... ...

Abstract	Kisspeptin, encoded by Kiss1, stimulates reproduction. In rodents, one Kiss1 population resides in the hypothalamic anterior ventral periventricular nucleus and neighboring rostral periventricular nucleus (AVPV/PeN). AVPV/PeN Kiss1 neurons are sexually dimorphic (greater in females), yet the mechanisms regulating their development and sexual differentiation remain poorly understood. Neonatal estradiol (E₂) normally defeminizes AVPV/PeN kisspeptin neurons, but emerging evidence suggests that developmental E₂ may also influence feminization of kisspeptin, although exactly when in development this process occurs is unknown. In addition, the obligatory role of GnRH signaling in governing sexual differentiation of Kiss1 or other sexually dimorphic traits remains untested. Here, we assessed whether AVPV/PeN Kiss1 expression is permanently impaired in adult hpg (no GnRH or E₂) or C57BL6 mice under different E₂ removal or replacement paradigms. We determined that 1) despite lacking GnRH signaling in development, marked sexual differentiation of Kiss1 still occurs in hpg mice; 2) adult hpg females, who lack lifetime GnRH and E₂ exposure, have reduced AVPV/PeN Kiss1 expression compared to wild-type females, even after chronic adulthood E₂ treatment; 3) E₂ exposure to hpg females during the pubertal period does not rescue their submaximal adult Kiss1 levels; and 4) in C57BL6 females, removal of ovarian E2 before the pubertal or juvenile periods does not impair feminization and maximal adult AVPV/PeN Kiss1 expression nor the ability to generate LH surges, indicating that puberty is not a critical period for Kiss1 development. Thus, sexual differentiation still occurs without GnRH, but GnRH or downstream E₂ signaling is needed sometime before juvenile development for complete feminization and maximal Kiss1 expression in adult females.
MeSH term(s)	Animals ; Anterior Thalamic Nuclei/cytology ; Anterior Thalamic Nuclei/drug effects ; Anterior Thalamic Nuclei/growth & development ; Anterior Thalamic Nuclei/metabolism ; Estradiol/pharmacology ; Estradiol/therapeutic use ; Estrogen Receptor alpha/chemistry ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Estrogen Replacement Therapy ; Estrogens/pharmacology ; Estrogens/therapeutic use ; Female ; Gonadotropin-Releasing Hormone/genetics ; Gonadotropin-Releasing Hormone/metabolism ; Hypogonadism/drug therapy ; Hypogonadism/metabolism ; Hypogonadism/pathology ; Intralaminar Thalamic Nuclei/cytology ; Intralaminar Thalamic Nuclei/drug effects ; Intralaminar Thalamic Nuclei/growth & development ; Intralaminar Thalamic Nuclei/metabolism ; Kisspeptins/biosynthesis ; Kisspeptins/genetics ; Kisspeptins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Nerve Tissue Proteins/agonists ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurons/cytology ; Neurons/drug effects ; Neurons/metabolism ; Ovariectomy/adverse effects ; Sex Differentiation/drug effects ; Sexual Development/drug effects ; Signal Transduction ; Thalamic Nuclei/cytology ; Thalamic Nuclei/drug effects ; Thalamic Nuclei/growth & development ; Thalamic Nuclei/metabolism ; Up-Regulation/drug effects
Chemical Substances	Estrogen Receptor alpha ; Estrogens ; Kiss1 protein, mouse ; Kisspeptins ; Nerve Tissue Proteins ; Gonadotropin-Releasing Hormone (33515-09-2) ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2013-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2013-1271
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Article ; Online: Effects of Selective Deletion of Tyrosine Hydroxylase from Kisspeptin Cells on Puberty and Reproduction in Male and Female Mice.

Stephens, Shannon B Z / Rouse, Melvin L / Tolson, Kristen P / Liaw, Reanna B / Parra, Ruby A / Chahal, Navi / Kauffman, Alexander S

eNeuro

2017 Volume 4, Issue 3

Abstract: The neuropeptide kisspeptin, encoded ... ...

Abstract	The neuropeptide kisspeptin, encoded by
MeSH term(s)	Animals ; Arcuate Nucleus of Hypothalamus/metabolism ; Body Weight/physiology ; Dopamine/metabolism ; Estradiol/administration & dosage ; Estradiol/metabolism ; Female ; Fertility/physiology ; Gonadotropins/metabolism ; Kisspeptins/genetics ; Kisspeptins/metabolism ; Longitudinal Studies ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons/enzymology ; Paraventricular Hypothalamic Nucleus/metabolism ; Reproduction/physiology ; Sexual Maturation/physiology ; Testosterone/metabolism ; Tyrosine 3-Monooxygenase/deficiency ; Tyrosine 3-Monooxygenase/genetics
Chemical Substances	Gonadotropins ; Kiss1 protein, mouse ; Kisspeptins ; Testosterone (3XMK78S47O) ; Estradiol (4TI98Z838E) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2017-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0150-17.2017
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Article ; Online: Inducible neuronal inactivation of Sim1 in adult mice causes hyperphagic obesity.

Tolson, Kristen P / Gemelli, Terry / Meyer, Donna / Yazdani, Umar / Kozlitina, Julia / Zinn, Andrew R

Endocrinology

2014 Volume 155, Issue 7, Page(s) 2436–2444

Abstract: Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 ... ...

Abstract	Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance. We previously showed that Sim1 heterozygous mice had normal numbers of PVN neurons that were hyporesponsive to melanocortin 4 receptor agonism and showed reduced oxytocin expression. Furthermore, conditional postnatal neuronal inactivation of Sim1 also caused hyperphagic obesity and decreased hypothalamic oxytocin expression. PVN projections to the hindbrain, where oxytocin is thought to act to modulate satiety, were anatomically intact in both Sim1 heterozygous and conditional knockout mice. These experiments provided evidence that Sim1 functions in energy balance apart from its role in hypothalamic development but did not rule out effects of Sim1 deficiency on postnatal hypothalamic maturation. To address this possibility, we used a tamoxifen-inducible, neural-specific Cre transgene to conditionally inactivate Sim1 in adult mice with mature hypothalamic circuitry. Induced Sim1 inactivation caused increased food and water intake and decreased expression of PVN neuropeptides, especially oxytocin and vasopressin, with no change in energy expenditure. Sim1 expression was not required for survival of PVN neurons. The results corroborate previous evidence that Sim1 acts physiologically as well as developmentally to regulate body weight. Inducible knockout mice provide a system for studying Sim1's physiologic function in energy balance and identifying its relevant transcriptional targets in the hypothalamus.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Body Weight/drug effects ; Bone Density Conservation Agents/pharmacology ; Eating/drug effects ; Energy Metabolism/drug effects ; Female ; Homeostasis/drug effects ; Hyperphagia/metabolism ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Neurons/metabolism ; Neuropeptides/metabolism ; Obesity/metabolism ; Oxytocin/metabolism ; Paraventricular Hypothalamic Nucleus/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Tamoxifen/pharmacology
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; Bone Density Conservation Agents ; Neuropeptides ; Repressor Proteins ; Sim1 protein, mouse ; Tamoxifen (094ZI81Y45) ; Oxytocin (50-56-6)
Language	English
Publishing date	2014-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2013-2125
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Article ; Online: Conditional knockout of kisspeptin signaling in brown adipose tissue increases metabolic rate and body temperature and lowers body weight.

Tolson, Kristen P / Marooki, Nuha / De Bond, Julie-Ann P / Walenta, Evelyn / Stephens, Shannon B Z / Liaw, Reanna B / Savur, Rishi / Wolfe, Andrew / Oh, Da Young / Smith, Jeremy T / Kauffman, Alexander S

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2019 Volume 34, Issue 1, Page(s) 107–121

Abstract: The peptide kisspeptin and its receptor, Kiss1r, act centrally to stimulate reproduction. Evidence indicates that kisspeptin signaling is also important for body weight (BW) and metabolism. We recently reported that Kiss1r KO mice develop obesity, along ... ...

Abstract	The peptide kisspeptin and its receptor, Kiss1r, act centrally to stimulate reproduction. Evidence indicates that kisspeptin signaling is also important for body weight (BW) and metabolism. We recently reported that Kiss1r KO mice develop obesity, along with reduced metabolism and energy expenditure, independent of estradiol levels. Outside the brain, Kiss1r is expressed in several metabolic tissues, including brown adipose tissue (BAT), but it is unknown which specific tissue is responsible for the metabolic phenotype in Kiss1r KOs. We first determined that global Kiss1r KO mice have significant alterations in body temperature and BAT thermogenic gene expression, perhaps contributing to their obesity. Next, to test whether kisspeptin signaling specifically in BAT influences BW, metabolism, or body temperature, we used Cre/lox technology to generate conditional Kiss1r knockout exclusively in BAT (BAT-Kiss1r KO). Unlike global Kiss1r KOs, BAT-Kiss1r KOs (lacking Kiss1r in just BAT) were not hypogonadal, as expected. Surprisingly, however, BAT-Kiss1r KOs of both sexes displayed significantly lower BW and adiposity than controls. This novel BAT-Kiss1r KO phenotype was of greater magnitude in females and was associated with improved glucose tolerance, increased metabolism, energy expenditure, and locomotor activity, along with increased body temperature and BAT gene expression, specifically Cox8b. Our findings suggest that the previously observed obesity and decreased metabolism in global Kiss1r KOs reflect impaired kisspeptin signaling in non-BAT tissues. However, the novel finding of increased metabolism and body temperature and lower BW in BAT-Kiss1r KOs reveal a previously unidentified role for endogenous kisspeptin signaling in BAT in modulating metabolic and thermogenic physiology.
MeSH term(s)	Adipocytes, Brown/metabolism ; Animals ; Body Temperature/genetics ; Body Temperature/physiology ; Body Weight/genetics ; Body Weight/physiology ; Energy Metabolism/genetics ; Energy Metabolism/physiology ; Genotype ; Mice ; Mice, Knockout ; Receptors, Kisspeptin-1/genetics ; Receptors, Kisspeptin-1/metabolism
Chemical Substances	Kiss1r protein, mouse ; Receptors, Kisspeptin-1
Language	English
Publishing date	2019-11-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201901600R
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