.2024 Feb 3;15(1):1030.

doi: 10.1038/s41467-024-45436-3.

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice

Fengwei Zhang¹, Wei Qiao^{2 3}, Ji-An Wei^{1 4}, Zhengyi Tao¹, Congjia Chen¹, Yefeng Wu⁵, Minghui Lin¹, Ka Man Carmen Ng¹, Li Zhang^{4 6}, Kelvin Wai-Kwok Yeung^{7 8}, Billy Kwok Chong Chow⁹

Affiliations

¹ School of Biological Sciences, the University of Hong Kong, Hong Kong, China.
² Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, the University of Hong Kong, Hong Kong, China. drqiao@hku.hk.
³ Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, the University of Hong Kong-Shenzhen Hospital, Shenzhen, China. drqiao@hku.hk.
⁴ Key Laboratory of CNS Regeneration (Ministry of Education), GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China.
⁵ Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, the University of Hong Kong, Hong Kong, China.
⁶ Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China.
⁷ Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, the University of Hong Kong-Shenzhen Hospital, Shenzhen, China. wkkyeung@hku.hk.
⁸ Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China. wkkyeung@hku.hk.
⁹ School of Biological Sciences, the University of Hong Kong, Hong Kong, China. bkcc@hku.hk.

PMID:38310104
PMCID: PMC10838336
DOI: 10.1038/s41467-024-45436-3

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice

Fengwei Zhang et al. Nat Commun.2024.

.2024 Feb 3;15(1):1030.

doi: 10.1038/s41467-024-45436-3.

Authors

Fengwei Zhang¹, Wei Qiao^{2 3}, Ji-An Wei^{1 4}, Zhengyi Tao¹, Congjia Chen¹, Yefeng Wu⁵, Minghui Lin¹, Ka Man Carmen Ng¹, Li Zhang^{4 6}, Kelvin Wai-Kwok Yeung^{7 8}, Billy Kwok Chong Chow⁹

Affiliations

¹ School of Biological Sciences, the University of Hong Kong, Hong Kong, China.
² Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, the University of Hong Kong, Hong Kong, China. drqiao@hku.hk.
³ Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, the University of Hong Kong-Shenzhen Hospital, Shenzhen, China. drqiao@hku.hk.
⁴ Key Laboratory of CNS Regeneration (Ministry of Education), GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China.
⁵ Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, the University of Hong Kong, Hong Kong, China.
⁶ Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China.
⁷ Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, the University of Hong Kong-Shenzhen Hospital, Shenzhen, China. wkkyeung@hku.hk.
⁸ Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China. wkkyeung@hku.hk.
⁹ School of Biological Sciences, the University of Hong Kong, Hong Kong, China. bkcc@hku.hk.

PMID:38310104
PMCID: PMC10838336
DOI: 10.1038/s41467-024-45436-3

Abstract

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Systemic SCT or SCTR KO results in metabolic dysfunction and bone loss.**
a Daily food intake of 10-week-old WT, Sct^−/−, and Sctr^−/− mice. Cumulative (b) and total (c) rebound food intake of 10-week-old WT, Sct^−/−, and Sctr^−/− mice after 16 h overnight fasting.d Weekly body weight changes of 4- to 20-week-old WT, Sct^−/−, and Sctr^−/− mice fed on standard rodent chow.e Body composition of 18-week-old WT, Sct^−/−, and Sctr^−/− mice.f Temporal changes of VO₂ and VCO₂ in 16-week-old WT, Sct^−/−, and Sctr^−/− mice.g Temporal changes of EE in 16-week-old WT, Sct^−/−, and Sctr^−/− mice (night: F_{(2, 12)} = 10.408, WTvs Sct^−/− (**P_genotype = 0.0022), WTvs Sctr^−/− (**P_genotype = 0.0028); day: F_{(2, 12)} = 0.916, WTvs Sct^−/− (P_genotype = 0.1737), WTvs Sctr^−/− (P_genotype = 0.3896)).h Serum NE levels in 20-week-old WT, Sct^−/−, and Sctr^−/− mice.i Representative μCT and H&E staining images showing the reduction in trabecular bone mass in the femurs of 20-week-old Sct^−/− and Sctr^−/− mice. Scale bar = 250 μm.j Corresponding measurements of (i): trabecular bone volume fraction (BV/TV), bone mineral density (BMD of TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular pattern factor (Tb.Pf), trabecular separation (Tb.Sp), and specific bone surface (BS/BV). BW, body weight. Numbers in parentheses in each graph indicate sample size. Box plots with whiskers from minima to maxima, the central line at the 50th percentile, and the ends of the box at the 25th and 75th percentiles.a,d,e,f Two-way ANOVA with Holm–Šídák multiple comparisons test.c,h,j One-way ANOVA with Holm–Šídák multiple comparisons test.g One-way ANCOVA with pairwise comparisons on adjusted means. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent SEM. Source data are provided as a Source Data file.

**Fig. 2. VMH-derived SCT regulate bone mass via SNS.**
a RNAscope in situ hybridization ofSct andNr5a1 in the VMH sections (n = 3). Scale bars = 50 μm.b Venn diagram of theSct- andNr5a1-positive cell distributions in (a).c Immunostaining of SCT in the VMH sections (n = 3). Scale bars = 100 μm.d Left: schematic of injecting AAV-ShSCT-eGFP/AAV-ShControl-eGFP bilaterally into the VMH of C57BL6/N mice. Right: representative image of eGFP expression in VMH (n = 5). Scale bars = 100 μm.e Reduced transcript levels ofSct in VMH after shRNA-mediated SCT KD.f Representative μCT images of femurs from 20-week-old ShSCT and ShCon littermates.g Corresponding measurements of (f). Representative femoral H&E staining (h) and lipid droplet statistics (i) of 20-week-old ShSCT and ShCon littermates. Arrows indicate lipids in bone marrow. Scale bar = 250 μm.j Left: TRAP staining of trabecular bone of 20-week-old ShSCT and ShCon littermates. Right: quantification of osteoclasts on the bone surface. Scale bars = 100 μm.k Left: calcein double labeling in trabecular bone. Right: MAR of 20-week-old ShSCT and ShCon littermates. Scale bar = 50 μm.l Left: schematic of injecting AAV-Cre-eGFP/AAV-eGFP bilaterally into the VMH of Sct^fl/fl mice. Right: representative image of eGFP expression in VMH (n = 5). Scale bar = 100 um.m Representative μCT images of femurs from 20-week-old SCT^VMH−/− and eGFP littermates.n Representative femoral H&E staining images of 20-week-old SCT^VMH−/− and eGFP littermates (n = 5). Arrows indicate lipids in bone marrow. Scale bar = 250 um.o, Corresponding measurements of (m).p Western blot of pCREB in VMH of 20-week-old ShSCT and ShCon littermates.q Serum NE levels of ShSCT and ShCon littermates. Numbers in parentheses in each graph indicate sample size. Box plots with whiskers from minima to maxima, the central line at the 50th percentile, and the ends of the box at the 25th and 75th percentiles. Two-tailed Student’st-test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent SEM. Source data are provided as a Source Data file.

**Fig. 3. Conditional KD of SCT in VMH leads to hyperphagia and obesity.**
a Daily food intake of 10-week-old ShSCT and ShCon littermates.b Rebound food intake of 10-week-old overnight fasted ShSCT and ShCon littermates.c Cumulative (left) and total (right) rebound food intake after SCT administration in 10-week-old overnight fasted ShSCT and ShCon littermates.d HypothalamicAgrp andPomc expression of 20-week-old ShSCT and ShCon littermates.e Left: weekly body weight changes of ShSCT and ShCon littermates fed on standard rodent chow. Black arrow indicates virus injection at 7 weeks of age. Right: representative photographs of 20-week-old mice.f Body composition of ShSCT and ShCon littermates.g WAT mass fractions of ShSCT and ShCon littermates.h Left: H&E staining of iWAT from ShSCT and ShCon littermates (n = 5). Right: adipocyte surface area distribution of iWAT. Scale bar = 100 μm.i Relative expression of beige adipocyte marker genes in the iWAT.j Blood insulin levels of ShSCT and ShCon littermates.k,l Glucose tolerance test of ShSCT and ShCon littermates.m,n Insulin tolerance test of ShSCT and ShCon littermates.o Daily food intake of 10-week-old SCT^VMH−/− and eGFP littermates.p Rebound food intake of 10-week-old overnight fasted SCT^VMH−/− and eGFP littermates.q Left: weekly body weight changes of SCT^VMH−/− and eGFP littermates fed on standard rodent chow. Black arrow indicates virus injection at 7 weeks of age. Right: representative photographs of 20-week-old mice.r Body composition of SCT^VMH−/− and eGFP littermates. AUC, area under the curve. Numbers in parentheses in each graph indicate sample size. Box plots with whiskers from minima to maxima, the central line at the 50th percentile, and the ends of the box at the 25th and 75th percentiles.a,b,e,f,k,m,o–r Two-way ANOVA with Holm–Šídák multiple comparisons test. (c) One-way ANOVA with Holm–Šídák multiple comparisons test.d,g,i,j,l,n Two-tailed Student’st-test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent SEM. Source data are provided as a Source Data file.

**Fig. 4. Conditional KD of SCT in VMH leads to thermogenic dysfunction.**
a Temporal changes of VO₂ and VCO₂ in 16-week-old ShSCT and ShCon littermates.b Temporal changes of EE in 16-week-old ShSCT and ShCon littermates.c Temporal changes of motor activity in 16-week-old ShSCT and ShCon littermates.d H&E staining of iBAT. Scale bar = 100 μm.e Mitochondria DNA contents in iBAT.f Relative expression of thermogenesis-related genes in iBAT.g The concentration (left) and total amount (right) of Ucp1 protein in iBAT depot.h Relative expression of inflammatory cytokine genes in iBAT.i Relative expression of sympathetic innervation-related genes in iBAT.j Western blot of TH in iBAT. XAMB, ambulatory activity count. XTOT, total horizontal motor activity. ZTOT, total vertical motor activity. Numbers in parentheses in each graph indicate sample size. Box plots with whiskers from minima to maxima, the central line at the 50th percentile, and the ends of the box at the 25th and 75th percentiles.a,c Two-way ANOVA with Holm–Šídák multiple comparisons test.b One-way ANCOVA with pairwise comparisons on adjusted means.e–j Two-tailed Student’st-test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent SEM. Source data are provided as a Source Data file.

**Fig. 5. Conditional KD of SCTR in VMH leads to osteopenia, hyperphagia, and obesity.**
a Double-immunostaining of SCTR and GFAP in the VMH sections (n = 5). Scale bar = 100 μm.b Left: schematic of injecting AAV-Cre- eGFP/AAV-eGFP bilaterally into the VMH of Sctr^fl/fl mice. Right: representative image of eGFP expression in VMH (n = 5). Scale bar = 100 μm.c Reduced transcript levels ofSctr in VMH after Cre-mediated SCTR KD.d Representative μCT images of femurs from 20-week-old SCTR^VMH−/− and eGFP littermates.e Corresponding measurements of (d).f Representative femoral H&E staining images of 20-week-old SCTR^VMH−/− and eGFP littermates. Scale bar = 250 μm.g Left: calcein double labeling in trabecular bone. Right: MAR of 20-week-old SCTR^VMH−/− and eGFP littermates. Scale bar = 50 μm.h Serum NE levels of SCTR^VMH−/− and eGFP littermates.i Daily food intake of 10-week-old SCTR^VMH−/− and eGFP littermates.j Rebound food intake of 10-week-old overnight fasted SCTR^VMH−/− and eGFP littermates.k Left: weekly body weight changes of SCTR^VMH−/− and eGFP littermates fed on standard rodent chow. Black arrow indicates virus injection at 7 weeks of age. Right: representative photographs of 20-week-old mice.l Body composition of 18-week-old SCTR^VMH−/− and eGFP littermates. Numbers in parentheses in each graph indicate sample size. Box plots with whiskers from minima to maxima, the central line at the 50th percentile, and the ends of the box at the 25th and 75th percentiles.c,e,g,h Two-tailed Student’st-test.i–l Two-way ANOVA with Holm–Šídák multiple comparisons test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent SEM. Source data are provided as a Source Data file.

**Fig. 6. Conditional KD of SCT in the VMH exacerbates obesity and osteopenia in DIO mice.**
a Left: weekly body weight changes of SCT^VMH−/− and eGFP littermates fed on HFD. Black arrow indicates virus injection at 7 weeks of age. The yellow shaded area indicates that the mice were fed HFD. Right: representative photographs of 20-week-old mice.b Body composition of 18-week-old HFD-fed SCT^VMH−/− and eGFP littermates.c Serum leptin levels in HFD-fed SCT^VMH−/− and eGFP littermates.d Daily food intake of 16-week-old HFD-fed SCT^VMH−/− and eGFP littermates.e Serum NE levels in HFD-fed SCT^VMH−/− and eGFP littermates.f Temporal changes of VCO₂ and VO₂ in 16-week-old HFD-fed SCT^VMH−/− and eGFP littermates.g Temporal changes of EE in 16-week-old HFD-fed SCT^VMH−/− and eGFP littermates.h Temporal changes of motor activity in 16-week-old HFD-fed SCT^VMH−/− and eGFP littermates.i Representative μCT images of femurs from 20-week-old HFD-fed SCT^VMH−/− and eGFP littermates.j Corresponding measurements of (i).k Representative femoral H&E staining images of 20-week-old HFD-fed SCT^VMH−/− and eGFP littermates. Scale bar = 250 μm. Numbers in parentheses in each graph indicate sample size. Box plots with whiskers from minima to maxima, the central line at the 50th percentile, and the ends of the box at the 25th and 75th percentiles.a,b,d,f,h Two-way ANOVA with Holm–Šídák multiple comparisons test.c,e,j Two-tailed Student’st-test.g One-way ANCOVA with pairwise comparisons on adjusted means. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent SEM. Source data are provided as a Source Data file.

**Fig. 7. SCT overexpression in VMH leads to bone mass increment.**
a Left: schematic of injecting rAAV-EF1α-SCT-mCherry or rAAV-EF1α-mCherry bilaterally into the VMH of C57BL6/N mice. Right: representative image of mCherry expression in VMH (n = 5). Scale bars = 100 μm.b Enhanced SCT levels in VMH after EF1α-mediated SCT overexpression.c Serum NE levels in SCToe and mCherry littermates.d Western blot of pCREB in VMH of 20-week-old SCToe and mCherry littermates.e Representative μCT images of femurs from 20-week-old SCToe and mCherry littermates.f Corresponding measurements of (e).g Representative femoral H&E staining images of 20-week-old SCToe and mCherry littermates. Scale bar = 250 μm.h Left: TRAP staining of trabecular bone of 20-week-old SCToe and mCherry littermates. Right: quantification of osteoclasts on the bone surface. Scale bars = 100 μm.i Daily food intake of 10-week-old SCToe and mCherry littermates.j Rebound food intake of 10-week-old overnight fasted SCToe and mCherry littermates.k Weekly body weight changes of SCToe and mCherry littermates fed on standard rodent chow. Black arrow indicates virus injection at 7 weeks of age.l Body composition of 18-week-old SCToe and mCherry littermates.m The schematic shows the mechanism by which VMH-derived SCT signaling regulates skeletal and metabolic homeostasis. Numbers in parentheses in each graph indicate sample size. Box plots with whiskers from minima to maxima, the central line at the 50th percentile, and the ends of the box at the 25th and 75th percentiles. (b,c,d,f,h) Two-tailed Student’st-test. (i,j,k,l) Two-way ANOVA with Holm–Šídák multiple comparisons test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent SEM. Source data are provided as a Source Data file.

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Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice

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Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice

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Conflict of interest statement

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