Gender-specific increase of bone mass by CART peptide treatment is ovary-dependent

Gerrits, Han; Bakker, Nicole E. C.; Laat, Cindy Jm van de Ven-de; Bourgondien, Freek Gm; Peddemors, Carolien; Litjens, Ralph Hgm; Kok, Han J; Vogel, G; Krajnc-Franken, Magda A. M.; Gossen, Jan A.

doi:10.1002/jbmr.500

Cited by 7 publications

(6 citation statements)

References 57 publications

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“…As part of the body composition analysis, and based on the known link between CART and bone remodeling [16] , [46] , effects of chronic CART introduction specifically into CART neurons in the Arc or LHA on bone parameters were also examined. Interestingly, neither introduction of CART into the Arc or LHA had any significant effect on both whole body BMD and BMC for either Cart cre/cre ( Fig.…”

Section: Resultsmentioning

confidence: 99%

CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis

Farzi

Heilbronn

et al. 2018

Molecular Metabolism

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ObjectiveThe cocaine- and amphetamine-regulated transcript (CART) codes for a pivotal neuropeptide important in the control of appetite and energy homeostasis. However, limited understanding exists for the defined effector sites underlying CART function, as discrepant effects of central CART administration have been reported.MethodsBy combining Cart-cre knock-in mice with a Cart adeno-associated viral vector designed using the flip-excision switch (AAV-FLEX) technology, specific reintroduction or overexpression of CART selectively in CART neurons in the arcuate nucleus (Arc) and lateral hypothalamic area (LHA), respectively, was achieved. The effects on energy homeostasis control were investigated.ResultsHere we show that CART neuron-specific reintroduction of CART into the Arc and LHA leads to distinct effects on energy homeostasis control. Specifically, CART reintroduction into the Arc of otherwise CART-deficient Cartcre/cre mice markedly decreased fat mass and body weight, whereas CART reintroduction into the LHA caused significant fat mass gain and lean mass loss, but overall unaltered body weight. The reduced adiposity in ArcCART;Cartcre/cre mice was associated with an increase in both energy expenditure and physical activity, along with significantly decreased Npy mRNA levels in the Arc but with no change in food consumption. Distinctively, the elevated fat mass in LHACART;Cartcre/cre mice was accompanied by diminished insulin responsiveness and glucose tolerance, greater spontaneous food intake, and reduced energy expenditure, which is consistent with the observed decrease of brown adipose tissue temperature. This is also in line with significantly reduced tyrosine hydroxylase (Th) and notably increased corticotropin-releasing hormone (Crh) mRNA expressions in the paraventricular nucleus (PVN).ConclusionsTaken together, these results identify catabolic and anabolic effects of CART in the Arc and LHA, respectively, demonstrating for the first time the distinct and region-specific functions of CART in controlling feeding and energy homeostasis.

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Section: Resultsmentioning

confidence: 99%

CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis

Farzi

Heilbronn

et al. 2018

Molecular Metabolism

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“…Interestingly, there are sex differences in CART peptide expression and function (Fagergren and Hurd, 1999, Rondini et al, 2004, Balkan et al, 2006, Gozen et al, 2007, Xu et al, 2010, Battistoni et al, 2011, Gerrits et al, 2011, Hostetler et al, 2011, Rodrigues et al, 2011, Bloem et al, 2012). Because of the findings that there are sex differences in (a) the effects of cocaine on DA in the NAc and (b) in CART peptide expression and function, we explored if there are sex differences in the effects of CART peptide on cocaine-induced LMA in rats.…”

Section: Introductionmentioning

confidence: 99%

Cocaine-and-Amphetamine Regulated Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: Lack of sex differences

et al. 2014

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Cocaine-and-Amphetamine Regulated Transcript peptide (CART peptide) is known for having an inhibitory effect on dopamine (DA)- and cocaine-mediated actions and is postulated to be a homeostatic, regulatory factor in the nucleus accumbens (NAc). Some sex differences in cocaine-mediated LMA and in the expression and function of CART peptide have been reported. However, it is not known if the inhibitory effect of CART peptide on cocaine-mediated locomotor activity (LMA) is sexually dimorphic. In this study, the effect of CART 55-102 on LMA due to intra-NAc DA and i.p. cocaine were determined in male and female Sprague-Dawley rats. The results show that CART 55-102 blunted or reduced both the DA- and cocaine-induced LMA in both males and females. In conclusion, CART peptide is effective in blunting DA- and cocaine-mediated LMA in both males and females.

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“…A gender-specific increase in bone mass was observed in response to peripheral, subcutaneous CART administration in female, but not male, wild-type and Cartpt-overexpressing transgenic mice [47]. Whereas the CART-induced increase in bone mass was ameliorated in ovariectomized animals, supplementation with estradiol did not restore the CART-induced increase in bone mass, suggesting an involvement of an unknown, ovary-dependent mechanism in maintenance of CART responsiveness and regulation of bone mass [47]. Whether such unknown mechanisms also modulate CART responsiveness in bovine ovarian granulosa cells is unknown.…”

Section: Folger Et Almentioning

confidence: 93%

“…Cartpt mutant mice display indices of osteoporosis [45], whereas female transgenic mice overexpressing Cartpt display an increase in bone mass [46]. A gender-specific increase in bone mass was observed in response to peripheral, subcutaneous CART administration in female, but not male, wild-type and Cartpt-overexpressing transgenic mice [47]. Whereas the CART-induced increase in bone mass was ameliorated in ovariectomized animals, supplementation with estradiol did not restore the CART-induced increase in bone mass, suggesting an involvement of an unknown, ovary-dependent mechanism in maintenance of CART responsiveness and regulation of bone mass [47].…”

Section: Folger Et Almentioning

confidence: 94%

Regulation of Granulosa Cell Cocaine and Amphetamine Regulated Transcript (CART) Binding and Effect of CART Signaling Inhibitor on Granulosa Cell Estradiol Production During Dominant Follicle Selection in Cattle1

Folger

Jimenez-Krassel

Ireland

et al. 2013

Biology of Reproduction

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We previously established a potential role for cocaine and amphetamine regulated transcript (CARTPT) in dominant follicle selection in cattle. CARTPT expression is elevated in subordinate versus dominant follicles, and treatment with the mature form of the CARTPT peptide (CART) decreases follicle-stimulating hormone (FSH)-stimulated granulosa cell estradiol production in vitro and follicular fluid estradiol and granulosa cell CYP19A1 mRNA in vivo. However, mechanisms that regulate granulosa cell CART responsiveness are not understood. In this study, we investigated hormonal regulation of granulosa cell CART-binding sites in vitro and temporal regulation of granulosa cell CART-binding sites in bovine follicles collected at specific stages of a follicular wave. We also determined the effect of inhibition of CART receptor signaling in vivo on estradiol production in future subordinate follicles. Granulosa cell CART binding in vitro was increased by FSH, and this induction was blocked by estrogen receptor antagonist treatment. In follicles collected in vivo at specific stages of a follicular wave, granulosa cell CART binding in the F2 (second largest), future subordinate follicle increased during dominant follicle selection. Injection into the F2 follicle (at onset of diameter deviation) of an inhibitor of the o/i subclass of G proteins (previously shown to block CART actions in vitro) resulted in increased follicular fluid estradiol concentrations in vivo. Collectively, results demonstrate hormonal regulation of granulosa cell CART binding in vitro and temporal regulation of CART binding in subordinate follicles during dominant follicle selection. Results also suggest that CART signaling may help suppress estradiol-producing capacity of the F2 (subordinate) follicle during this time period.

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Gender-specific increase of bone mass by CART peptide treatment is ovary-dependent

Cited by 7 publications

References 57 publications

CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis

CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis

Cocaine-and-Amphetamine Regulated Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: Lack of sex differences

Regulation of Granulosa Cell Cocaine and Amphetamine Regulated Transcript (CART) Binding and Effect of CART Signaling Inhibitor on Granulosa Cell Estradiol Production During Dominant Follicle Selection in Cattle1

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