Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production
Increased glucocorticoid (GC) levels act as a master contributor to central obesity in estrogen-depleted females; however, what factors cause their increased GC production is unclear. Given (1) liver fibroblast growth factor 21 (FGF21) and GCs regulate each other’s production in a feed-forward loop,...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/14922 |
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| author | Jiayu Xu Xinyu Shao Haozhe Zeng Chengxi Wang Jiayi Li Xiaoqin Peng Yong Zhuo Lun Hua Fengyan Meng Xingfa Han |
| author_facet | Jiayu Xu Xinyu Shao Haozhe Zeng Chengxi Wang Jiayi Li Xiaoqin Peng Yong Zhuo Lun Hua Fengyan Meng Xingfa Han |
| author_sort | Jiayu Xu |
| collection | DOAJ |
| description | Increased glucocorticoid (GC) levels act as a master contributor to central obesity in estrogen-depleted females; however, what factors cause their increased GC production is unclear. Given (1) liver fibroblast growth factor 21 (FGF21) and GCs regulate each other’s production in a feed-forward loop, and (2) circulating FGF21 and GCs are parallelly increased in menopausal women and ovariectomized mice, we thus hypothesized that elevation of hepatic FGF21 secretion causes increased GGs production in estrogen-depleted females. Using the ovariectomized mice as a model for menopausal women, we found that ovariectomy (OVX) increased circulating corticosterone levels, which in turn increased visceral adipose <i>Hsd11b1</i> expression, thus causing visceral obesity in females. In contrast, liver-specific FGF21 knockout (FGF21 LKO) completely reversed OVX-induced high GCs and high visceral adipose <i>Hsd11b1</i> expression, thus abrogating OVX-induced obesity in females. Even though FGF21 LKO failed to rescue OVX-induced dyslipidemia, hepatic steatosis, and insulin resistance. What’s worse, FGF21 LKO even further exacerbated whole-body glucose metabolic dysfunction as evidenced by more impaired glucose and pyruvate tolerance and worsened insulin resistance. Mechanically, we found that FGF21 LKO reduced circulating insulin levels, thus causing the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes in OVX mice. Collectively, our results suggest that liver FGF21 plays an essential role in mediating OVX-induced central obesity by promoting GC production. However, lack of liver FGF21 signaling reduces insulin production and in turn causes the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes, highlighting a detrimental role for hepatic FGF21 signals in mediating the development of central obesity but a beneficial role in preventing metabolic abnormality from further exacerbation in estrogen-depleted females. |
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| issn | 1661-6596 1422-0067 |
| language | English |
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| spelling | doaj.art-d09b8ac62b2643e5b193c6aa8420d5c52023-11-19T14:32:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124191492210.3390/ijms241914922Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone ProductionJiayu Xu0Xinyu Shao1Haozhe Zeng2Chengxi Wang3Jiayi Li4Xiaoqin Peng5Yong Zhuo6Lun Hua7Fengyan Meng8Xingfa Han9College of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaCollege of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaCollege of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaCollege of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaCollege of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaCollege of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaInstitute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611134, ChinaInstitute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611134, ChinaCollege of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaCollege of Life Science, Sichuan Agricultural University, Ya’an 625014, ChinaIncreased glucocorticoid (GC) levels act as a master contributor to central obesity in estrogen-depleted females; however, what factors cause their increased GC production is unclear. Given (1) liver fibroblast growth factor 21 (FGF21) and GCs regulate each other’s production in a feed-forward loop, and (2) circulating FGF21 and GCs are parallelly increased in menopausal women and ovariectomized mice, we thus hypothesized that elevation of hepatic FGF21 secretion causes increased GGs production in estrogen-depleted females. Using the ovariectomized mice as a model for menopausal women, we found that ovariectomy (OVX) increased circulating corticosterone levels, which in turn increased visceral adipose <i>Hsd11b1</i> expression, thus causing visceral obesity in females. In contrast, liver-specific FGF21 knockout (FGF21 LKO) completely reversed OVX-induced high GCs and high visceral adipose <i>Hsd11b1</i> expression, thus abrogating OVX-induced obesity in females. Even though FGF21 LKO failed to rescue OVX-induced dyslipidemia, hepatic steatosis, and insulin resistance. What’s worse, FGF21 LKO even further exacerbated whole-body glucose metabolic dysfunction as evidenced by more impaired glucose and pyruvate tolerance and worsened insulin resistance. Mechanically, we found that FGF21 LKO reduced circulating insulin levels, thus causing the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes in OVX mice. Collectively, our results suggest that liver FGF21 plays an essential role in mediating OVX-induced central obesity by promoting GC production. However, lack of liver FGF21 signaling reduces insulin production and in turn causes the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes, highlighting a detrimental role for hepatic FGF21 signals in mediating the development of central obesity but a beneficial role in preventing metabolic abnormality from further exacerbation in estrogen-depleted females.https://www.mdpi.com/1422-0067/24/19/14922FGF21overiectomycentral obesitycorticosteroneinsulinmetabolic syndromes |
| spellingShingle | Jiayu Xu Xinyu Shao Haozhe Zeng Chengxi Wang Jiayi Li Xiaoqin Peng Yong Zhuo Lun Hua Fengyan Meng Xingfa Han Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production International Journal of Molecular Sciences FGF21 overiectomy central obesity corticosterone insulin metabolic syndromes |
| title | Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production |
| title_full | Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production |
| title_fullStr | Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production |
| title_full_unstemmed | Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production |
| title_short | Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production |
| title_sort | hepatic specific fgf21 knockout abrogates ovariectomy induced obesity by reversing corticosterone production |
| topic | FGF21 overiectomy central obesity corticosterone insulin metabolic syndromes |
| url | https://www.mdpi.com/1422-0067/24/19/14922 |
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