A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance
Open accessAbstract
AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders.
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Written from the paper’s full text.
TL;DR
Central BMP8B promotes brown adipose tissue thermogenesis and white adipose tissue browning through a hypothalamic VMH–LHA circuit in which AMPK inhibition in the VMH increases glutamatergic signaling and orexin/OX1R activity in the LHA. The thermogenic effect is sexually dimorphic, requires ovarian estrogens, and is absent in orexin-null mice.
Key findings
- Central BMP8B’s thermogenic effect is sexually dimorphic: male rats showed no increase in body or BAT temperature after 2 hr i.c.v. BMP8B, whereas ovariectomized (OVX) females lost the response and estradiol replacement restored it. OVX rats gained more weight (sham: 23.1 ± 2.38 g versus OVX: 71.3 ± 28 g; p < 0.001) and were hyperphagic (sham: 14.87 ± 0.31 g/day versus OVX: 17.70 ± 0.49 g/day; p < 0.01).
- BMP8B in the VMH, but not the LHA, produced feeding-independent weight loss, increased body temperature and energy expenditure, reduced respiratory quotient, decreased phosphorylated AMPKα and ACCα in the VMH, increased BAT UCP1 and thermogenic markers, and promoted WAT browning.
- BMP8B increased orexin mRNA in the LHA via AMPK inhibition in the VMH: constitutively active AMPKα in the VMH reversed BMP8B’s thermogenic effect and reduced OX expression; the OX1R antagonist SB-334867 blunted BMP8B thermogenesis at 4 and 6 hr; and BMP8B’s thermogenic effect was absent in OX-null mice, although AMPK signaling decreased in the VMH of both WT and OX KO mice.
- VGLUT2 knockdown in the LHA blunted BMP8B effects on core and BAT temperature, OX mRNA, and BAT UCP1; pAMPK was reduced in both GFP and shVGLUT2 groups (vehicle GFP: 100 ± 18.6 versus BMP8B GFP: 42.6 ± 12.3, p < 0.05; vehicle shVGLUT2: 100 ± 10.7 versus BMP8B shVGLUT2: 62.9 ± 12.5, p < 0.05), indicating glutamatergic signaling downstream of AMPK.
Methods
- Adult female and male Sprague-Dawley rats (200–250 g), adult female OX/Hcrt-null mice and WT littermates (8–10 weeks) were used. Experiments included i.c.v. and nucleus-specific VMH/LHA treatments, OVX with or without estradiol replacement, stereotaxic adenoviral AMPKα-CA/GFP or lentiviral shVGLUT2/GFP delivery, OX1R antagonist SB-334867, and exposure to 23°C or 4°C.
- Outcomes included body and BAT temperature, energy expenditure, respiratory quotient, locomotor activity, NMR body composition, food intake and body weight, plus molecular analyses by in situ hybridization, western blotting, real-time PCR, and immunohistochemistry for AMPK/ACC, UCP1, OX, and VGLUT2.
- Data are expressed as mean ± SEM; statistical significance used Student’s t test for two groups or ANOVA with post hoc two-tailed Bonferroni test for more than two groups, with p < 0.05 considered significant.
Limitations
- The paper has no explicit limitations section. It states that whether VGLUT2 in AMPK-expressing neurons mediates the effect is unclear, whether the mechanism is exclusive to BMP8B or shared by leptin, thyroid hormones, estradiol, GLP-1, or nicotine is unknown, and sleep/arousal effects were not specifically addressed.
- Evident from the text: the mechanistic work is largely in female rats/mice, and male rats did not respond to central BMP8B, so generalizability to males is limited. Several reported effects are trends rather than significant, including reduced adiposity after VMH BMP8B (p = 0.07), increased locomotor activity after VMH BMP8B (p = 0.07), and WAT browning marker tendencies.
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0 of 19 cited sources checked · 0 supported · 0 flagged
- Findingown data
OVX rats with E2 replacement responded normally to BMP8B.
“Of note, OVX rats with E2 replacement responded normally to BMP8B (Figures 1C and 1D).”
Quote in the paperSubstantial claim - Findingown data
OVX totally abolished the thermogenic action of central BMP8B at both body and BAT temperature levels in female rats.
“While central administration of BMP8B to sham controls induced a clear thermogenic action, OVX totally abolished it at both body and BAT temperature levels.”
Quote in the paperSubstantial claim - Findingown data
Male rats did not show an increase in body or BAT temperature after 2 hr of i.c.v. BMP8B.
“Our data showed that after 2 hr of an intracerebroventricular (i.c.v.) injection of BMP8B, male rats did not show an increase in either body (Figure 1A) or BAT temperature (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
BMP8B in the VMH is associated with a trend (p = 0.07) to reduce adiposity without changes in lean mass.
“The action of BMP8B in the VMH was associated with a trend (p = 0.07) to reduce adiposity without changes in the lean mass (Figure 2C).”
Quote in the paperNot a substantial claim - Findingown data
VMH administration of BMP8B decreased phosphorylated levels of AMPKα in the VMH.
“We found that VMH administration of BMP8B decreased the phosphorylated levels of AMPKα (pAMPKα) and its downstream target acetyl-CoA carboxylase alpha (pACCα); no changes were found in total levels of AMPKα1, AMPKα2, ACCα, and fatty acid synthase (FAS) (Figure 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in phosphorylated AMPKα levels reflect changes in AMPK activity in the VMH.
- Findingown data
No changes in locomotor activity were found when BMP8B was administered either in the VMH or the LHA.
“No changes in locomotor activity (LA) were found when BMP8B was administered either in the VMH or the LHA (Figures 2K and 2L), although a non-significant trend (p = 0.07) for increased LA was detected in VMH BMP8B-treated rats.”
Quote in the paperNot a substantial claim - Findingown data
BMP8B-treated rats in the VMH displayed a brown-like pattern in WAT.
“Histological analysis of WAT showed that BMP8B-treated rats in the VMH displayed a brown-like pattern, associated with increased UCP1 immunostaining and decreased adipocyte area (Figure 3H).”
Quote in the paperSubstantial claim - Findingown data
BMP8B-treated rats in the VMH displayed increased UCP1 immunostaining in WAT.
“Histological analysis of WAT showed that BMP8B-treated rats in the VMH displayed a brown-like pattern, associated with increased UCP1 immunostaining and decreased adipocyte area (Figure 3H).”
Quote in the paperSubstantial claim - Findingown data
BMP8B in the VMH increases EE.
“Moreover, BMP8B in the VMH, but not in the LHA, increased EE (Figures 2G and 2H) and reduced the respiratory quotient (RQ; Figures 2I and 2J).”
Quote in the paperSubstantial claim - Findingown data
BMP8B-treated rats in the VMH displayed decreased adipocyte area in WAT.
“Histological analysis of WAT showed that BMP8B-treated rats in the VMH displayed a brown-like pattern, associated with increased UCP1 immunostaining and decreased adipocyte area (Figure 3H).”
Quote in the paperSubstantial claim - Findingown data
BMP8B in the LHA has no effect on body temperature.
“No effect on body temperature was found when BMP8B was given in the LHA (Figure 2F).”
Quote in the paperSubstantial claim - Findingown data
Constitutive activation of AMPK in the VMH was associated with a reduction in the expression of OX in the LHA.
“This effect also was associated with a reduction in the expression of OX in the LHA (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
i.c.v. administration of BMP8B elevated OX mRNA expression in the LHA.
“Our data showed that i.c.v. administration of BMP8B increased body temperature (vehicle i.c.v.: −0.1°C ± 0.09°C versus BMP8B i.c.v.: 0.48°C ± 0.07°C; p < 0.001) and UCP1 protein levels in BAT (vehicle i.c.v.: 100% ± 14.6% versus BMP8B i.c.v.: 137.8% ± 10.1%; p < 0.05), in association with elevated OX mRNA expression in the LHA (Figure S3A).”
Quote in the paperSubstantial claim - Findingown data
BMP8B within the VMH increased mRNA expression of thermogenic markers in BAT.
“BMP8B within the VMH also increased UCP1 protein levels (Figure 3B) and the mRNA expression of thermogenic markers (Figure 3C) in the brown fat.”
Quote in the paperSubstantial claim - Findingown data
No changes were found in WAT when BMP8B was given in the LHA.
“No changes were found when BMP8B was given in the LHA (Figure 3J).”
Quote in the paperSubstantial claim - Findingown data
LHA administration of BMP8B did not affect AMPK signaling in the VMH.
“When administered in the LHA, BMP8B did not affect either AMPK signaling in the VMH (Figure 3D) or UCP1 protein levels (Figure 3E) or the mRNA expression of thermogenic markers (Figure 3F) in the BAT.”
Quote in the paperSubstantial claim - Findingown data
BMP8B in the VMH reduces RQ.
“Moreover, BMP8B in the VMH, but not in the LHA, increased EE (Figures 2G and 2H) and reduced the respiratory quotient (RQ; Figures 2I and 2J).”
Quote in the paperSubstantial claim - Findingown data
LHA administration of BMP8B did not affect UCP1 protein levels in BAT.
“When administered in the LHA, BMP8B did not affect either AMPK signaling in the VMH (Figure 3D) or UCP1 protein levels (Figure 3E) or the mRNA expression of thermogenic markers (Figure 3F) in the BAT.”
Quote in the paperSubstantial claim - Findingown data
VMH administration of BMP8B decreased phosphorylated levels of ACCα in the VMH.
“We found that VMH administration of BMP8B decreased the phosphorylated levels of AMPKα (pAMPKα) and its downstream target acetyl-CoA carboxylase alpha (pACCα); no changes were found in total levels of AMPKα1, AMPKα2, ACCα, and fatty acid synthase (FAS) (Figure 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in phosphorylated AMPKα levels reflect changes in AMPK activity in the VMH.
- Findingown data
BMP8B in the LHA promotes no changes in fat or lean mass.
“BMP8B in the LHA promoted no changes either in fat or lean mass (Figure 2D).”
Quote in the paperSubstantial claim - Findingown data
BMP8B in the VMH promotes feeding-independent weight loss.
“When given in the VMH, BMP8B promoted a feeding-independent weight loss (Figure 2A; initial body weight vehicle VMH: 240.0 ± 4.4 g versus BMP8B VMH: 237.5 ± 4.0 g; non-significant); no effect was observed when BMP8B was injected in the LHA (Figure 2B; initial body weight vehicle LHA: 233.0 ± 3.1 g versus BMP8B LHA: 235.1 ± 1.8 g; non-significant).”
Quote in the paperSubstantial claim - Findingown data
i.c.v. administration of BMP8B increased UCP1 protein levels in BAT.
“Our data showed that i.c.v. administration of BMP8B increased body temperature (vehicle i.c.v.: −0.1°C ± 0.09°C versus BMP8B i.c.v.: 0.48°C ± 0.07°C; p < 0.001) and UCP1 protein levels in BAT (vehicle i.c.v.: 100% ± 14.6% versus BMP8B i.c.v.: 137.8% ± 10.1%; p < 0.05), in association with elevated OX mRNA expression in the LHA (Figure S3A).”
Quote in the paperSubstantial claim - Findingown data
BMP8B protected against loss of core and BAT temperature when given at 4°C.
“Our data showed that BMP8B protected against the loss of both core (Figure 1E) and BAT (Figure 1F) temperature when given at 4°C.”
Quote in the paperSubstantial claim - Findingown data
BMP8B in the LHA has no effect on weight.
“When given in the VMH, BMP8B promoted a feeding-independent weight loss (Figure 2A; initial body weight vehicle VMH: 240.0 ± 4.4 g versus BMP8B VMH: 237.5 ± 4.0 g; non-significant); no effect was observed when BMP8B was injected in the LHA (Figure 2B; initial body weight vehicle LHA: 233.0 ± 3.1 g versus BMP8B LHA: 235.1 ± 1.8 g; non-significant).”
Quote in the paperSubstantial claim - Findingown data
BMP8B within the VMH increased UCP1 protein levels in BAT.
“BMP8B within the VMH also increased UCP1 protein levels (Figure 3B) and the mRNA expression of thermogenic markers (Figure 3C) in the brown fat.”
Quote in the paperSubstantial claim - Findingown data
Constitutive activation of AMPK in the VMH reversed the thermogenic effect of BMP8B at both whole body and BAT levels.
“When given to BMP8B-treated rats, constitutive activation of AMPK in the VMH reversed the thermogenic effect of BMP8B at both whole body (Figure 4C) and BAT levels (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
VMH administration of BMP8B increased mRNA levels of OX in the LHA.
“Our data showed that, when given in that nucleus, BMP8B also increased the mRNA levels of OX in the LHA (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
BMP8B in the VMH induces a marked elevation in body temperature.
“Treatment with BMP8B within the VMH induced a marked elevation in body temperature, which was consistent during the whole period of administration (Figure 2E).”
Quote in the paperSubstantial claim - Findingown data
i.c.v. administration of BMP8B increased body temperature.
“Our data showed that i.c.v. administration of BMP8B increased body temperature (vehicle i.c.v.: −0.1°C ± 0.09°C versus BMP8B i.c.v.: 0.48°C ± 0.07°C; p < 0.001) and UCP1 protein levels in BAT (vehicle i.c.v.: 100% ± 14.6% versus BMP8B i.c.v.: 137.8% ± 10.1%; p < 0.05), in association with elevated OX mRNA expression in the LHA (Figure S3A).”
Quote in the paperSubstantial claim - Findingown data
LHA administration of BMP8B did not affect mRNA expression of thermogenic markers in BAT.
“When administered in the LHA, BMP8B did not affect either AMPK signaling in the VMH (Figure 3D) or UCP1 protein levels (Figure 3E) or the mRNA expression of thermogenic markers (Figure 3F) in the BAT.”
Quote in the paperSubstantial claim - Findingown data
shVGLUT2 lentiviruses normalized the BMP8B-induced increase in OX mRNA levels in the LHA.
“Those functional readouts were associated with a normalization in the BMP8B-induced increase in OX mRNA levels in the LHA (Figure 7D) and UCP1 protein concentration in the BAT (Figures 7E and 7F).”
Quote in the paperSubstantial claim- Rests on an assumption: The shVGLUT2 lentiviruses specifically reduce VGLUT2 in the LHA without off-target effects.
- Findingown data
After i.c.v. BMP8B, pAMPK levels were reduced in the VMH in both WT and OX KO mice at 4°C.
“Those effects were associated with a similar effect in the VMH in both genotypes, i.e., reduced pAMPK levels, after the i.c.v. injection of BMP8B (Figures 6D and 6E).”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in phosphorylated AMPKα levels reflect changes in AMPK activity in the VMH.
- Findingown data
Central BMP8B increased body temperature in WT mice.
“When given centrally, BMP8B increased body temperature (Figure 5A) and BAT temperature (Figure 5B) in WT, but not in OX knockout (KO) mice.”
Quote in the paperSubstantial claim - Findingown data
OX KO mice are cold intolerant when exposed to 4°C for just 12 hr.
“Our data showed that null mice were cold intolerant when exposed to 4°C for just 12 hr (Figure 6A).”
Quote in the paperSubstantial claim - Findingown data
Central BMP8B's thermogenic effect is absent in OX-null mice.
“Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice.”
- Also stated in: § OX Mediates the Thermogenic Effect of Central BMP8B Independently of Environmental Temperature · plain
“When given centrally, BMP8B increased body temperature (Figure 5A) and BAT temperature (Figure 5B) in WT, but not in OX knockout (KO) mice.”
Quote in the paperSubstantial claim - Also stated in: § OX Mediates the Thermogenic Effect of Central BMP8B Independently of Environmental Temperature · plain
- Findingown data
WT mice displayed elevated UCP1 protein levels in BAT after i.c.v. BMP8B at 4°C.
“However, accordingly with the temperature data, while WT mice displayed elevated UCP1 protein levels in BAT (Figure 6F), KO mice did not (Figure 6G).”
Quote in the paperSubstantial claim - Findingown data
shVGLUT2 lentiviruses totally blunted central BMP8B effects on both core and BAT temperatures.
“Our data showed that shVGLUT2 lentiviruses totally blunted central BMP8B effects on both core and BAT temperatures (Figures 7B and 7C).”
Quote in the paperSubstantial claim- Rests on an assumption: The shVGLUT2 lentiviruses specifically reduce VGLUT2 in the LHA without off-target effects.
- Findingown data
Central BMP8B increased BAT temperature in WT mice.
“When given centrally, BMP8B increased body temperature (Figure 5A) and BAT temperature (Figure 5B) in WT, but not in OX knockout (KO) mice.”
Quote in the paperSubstantial claim - Findingown data
OX KO mice did not display elevated UCP1 protein levels in BAT after i.c.v. BMP8B at 4°C.
“However, accordingly with the temperature data, while WT mice displayed elevated UCP1 protein levels in BAT (Figure 6F), KO mice did not (Figure 6G).”
Quote in the paperSubstantial claim - Findingown data
AMPK signaling was decreased in the VMH of both WT and OX KO mice after central BMP8B.
“Notably, AMPK signaling was decreased in the VMH of both WT (Figure 5C) and OX KO mice (Figure 5D), suggesting again that AMPK in the VMH is upstream of OX in the LHA.”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in phosphorylated AMPKα levels reflect changes in AMPK activity in the VMH.
- Findingown data
WT mice kept at 4°C had a full thermogenic response to central BMP8B.
“Our data demonstrated that, while WT mice kept at 4°C had a full thermogenic response to central BMP8B (similarly to rats; Figures 1E and 1F), OX KO mice failed to respond (Figures 6B and 6C).”
Quote in the paperSubstantial claim - Findingown data
OX KO mice kept at 4°C failed to respond to central BMP8B.
“Our data demonstrated that, while WT mice kept at 4°C had a full thermogenic response to central BMP8B (similarly to rats; Figures 1E and 1F), OX KO mice failed to respond (Figures 6B and 6C).”
Quote in the paperSubstantial claim - Findingown data
SB-334867 did not have any impact on the BMP8B-induced decrease in AMPK signaling in the VMH.
“Of note, SB-334867 did not have any impact on the BMP8B-induced decrease in AMPK signaling in the VMH (Figure 4G), suggesting that AMPK in that nucleus operates upstream of OX1R signaling in this pathway.”
Quote in the paperSubstantial claim - Findingown data
The thermogenic effect of both central and VMH-specific BMP8B administration correlated with increased OX expression in the LHA.
“Interestingly, the thermogenic effect of both central and VMH-specific BMP8B administration correlated with increased OX expression in the LHA.”
Quote in the paperSubstantial claim - Findingown data
The expression of BMP type I receptors ALK4, ALK5, and ALK7 in the VMH and LHA was demonstrated by real-time RT-PCR analysis.
“Noteworthy, the expression of BMP type I receptors ALK4, ALK5, and ALK7 in those nuclei was demonstrated by real-time RT-PCR analysis (Figure S2A) of dissected VMH and LHA, whose specificity was controlled by analysis of the specific markers steroidogenic factor 1 (SF1) and OX, respectively (Figure S2B).”
Quote in the paperSubstantial claim - Findingown data
pAMPK protein levels were reduced in both the GFP- and the shVGLUT2-treated groups after BMP8B.
“Of note, pAMPK protein levels were reduced in both the GFP- and the shVGLUT2-treated groups (vehicle GFP: 100 ± 18.6 versus BMP8B GFP: 42.6 ± 12.3, p < 0.05; and vehicle shVGLUT2: 100 ± 10.7 versus BMP8B shVGLUT2: 62.9 ± 12.5, p < 0.05), indicating that glutamatergic signaling was acting downstream of AMPK.”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in phosphorylated AMPKα levels reflect changes in AMPK activity in the VMH.
- Findingown data
VGLUT2 inhibition in the LHA totally blunted BMP8B's effect on OX expression in the LHA.
“Notably, VGLUT2 inhibition totally blunted BMP8B’s effects on temperature, OX expression in the LHA, and UCP1 expression in BAT.”
Quote in the paperSubstantial claim - Findingown data
BMP8B induces browning of WAT.
“BMP8B also induces browning of white adipose tissue (WAT)”
Quote in the paperSubstantial claim - Findingown data
shVGLUT2 lentiviruses normalized the BMP8B-induced increase in UCP1 protein concentration in BAT.
“Those functional readouts were associated with a normalization in the BMP8B-induced increase in OX mRNA levels in the LHA (Figure 7D) and UCP1 protein concentration in the BAT (Figures 7E and 7F).”
Quote in the paperSubstantial claim- Rests on an assumption: The shVGLUT2 lentiviruses specifically reduce VGLUT2 in the LHA without off-target effects.
- Findingown data
VGLUT2 inhibition in the LHA totally blunted BMP8B's effect on temperature.
“Notably, VGLUT2 inhibition totally blunted BMP8B’s effects on temperature, OX expression in the LHA, and UCP1 expression in BAT.”
Quote in the paperSubstantial claim - Findingown data
VGLUT2 inhibition in the LHA totally blunted BMP8B's effect on UCP1 expression in BAT.
“Notably, VGLUT2 inhibition totally blunted BMP8B’s effects on temperature, OX expression in the LHA, and UCP1 expression in BAT.”
Quote in the paperSubstantial claim - Findingown data
Chronic treatment with BMP8B, specifically within the VMH, tended to increase LA.
“our data show that chronic treatment with BMP8B, specifically within the VMH, tended to increase LA”
Quote in the paperNot a substantial claim - Findingnone given
Endogenous ovarian steroids are relevant in the modulation of BMP8B thermogenic actions.
“and in particular the relevance of endogenous ovarian steroids in the modulation of BMP8B thermogenic actions”
Quote in the paperNot a substantial claim - Findingown data
The present results do not show an impact on feeding.
“The present results do not show an impact on feeding”
Quote in the paperSubstantial claim - Findingnone given
The thermogenic effect of BMP8B is sexually dependent.
“Second, the sexual dependency of the thermogenic effect of BMP8B”
Quote in the paperNot a substantial claim - Interpretationown data
The thermogenic action of BMP8B depends on physiological levels of ovarian estrogens.
“Overall, these data indicated that the thermogenic action of BMP8B shows a sexual dimorphism and depends on physiological levels of ovarian estrogens.”
Quote in the paperSubstantial claim- Rests on an assumption: The OVX model with E2 replacement restores physiological estradiol levels.
- Premisecitation
BMP8B acts centrally.
“Given that BMP8B acts centrally, its thermogenic effect is dependent upon the activation status of AMPK in the VMH, and it increases neuronal activation in the LHA (Whittle et al., 2012), we aimed to uncover the neuronal circuitry linking energy sensors and neuropeptides involved in the thermogenic effect of central BMP8B.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whittle et al., 2012 source
Not checked in the free run.
- Interpretationown data
The thermogenic action of BMP8B is sexually dimorphic.
“its thermogenic effect is sexually dimorphic (only observed in females)”
- Also stated in: § The Thermogenic Effect of Central BMP8B Is Sexually Dimorphic · hedged
“Overall, these data indicated that the thermogenic action of BMP8B shows a sexual dimorphism and depends on physiological levels of ovarian estrogens.”
Quote in the paperSubstantial claim - Also stated in: § The Thermogenic Effect of Central BMP8B Is Sexually Dimorphic · hedged
- Premisecitation
Central BMP8B exerts a robust thermogenic effect in females.
“Recent evidence has demonstrated that central BMP8B exerts a robust thermogenic effect in females (Whittle et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whittle et al., 2012 source
Not checked in the free run.
- Premisecitation
BMP8B's thermogenic effect is dependent upon the activation status of AMPK in the VMH.
“Given that BMP8B acts centrally, its thermogenic effect is dependent upon the activation status of AMPK in the VMH, and it increases neuronal activation in the LHA (Whittle et al., 2012), we aimed to uncover the neuronal circuitry linking energy sensors and neuropeptides involved in the thermogenic effect of central BMP8B.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whittle et al., 2012 source
Not checked in the free run.
- Premisecitation
BMP8B increases neuronal activation in the LHA.
“Given that BMP8B acts centrally, its thermogenic effect is dependent upon the activation status of AMPK in the VMH, and it increases neuronal activation in the LHA (Whittle et al., 2012), we aimed to uncover the neuronal circuitry linking energy sensors and neuropeptides involved in the thermogenic effect of central BMP8B.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whittle et al., 2012 source
Not checked in the free run.
- Study design and conductown data
SB-334867 alone had no effect on body temperature at any examined time.
“SB-334867 alone had no effect on body temperature at any examined time (2 hr vehicle vehicle: 0.19°C ± 0.08°C versus vehicle SB-334867: 0.20 ± 0.07, non-significant; 4 hr vehicle vehicle: 0.40°C ± 0.14°C versus vehicle SB-334867: 0.39 ± 0.17, non-significant; and 6 hr vehicle vehicle: 0.26°C ± 0.13°C versus vehicle SB-334867: 0.23 ± 0.19, non-significant).”
Quote in the paperSubstantial claim - Interpretationreasoning
Central BMP8B action on OX expression is mediated by the inhibition of AMPK in the VMH.
“These results suggest that central BMP8B action on OX expression is mediated by the inhibition of AMPK in the VMH.”
Quote in the paperSubstantial claim - Interpretationown data
BMP8B in the VMH acts upstream in the LHA to promote OX expression.
“These results suggested that BMP8B in the VMH acts upstream in the LHA to promote OX expression.”
Quote in the paperSubstantial claim - Interpretationown data
BMP8B's actions on the VMH are direct and not mediated by a previous effect on the LHA.
“This evidence suggests that BMP8B’s actions on the VMH are direct and not mediated by a previous effect on the LHA.”
Quote in the paperSubstantial claim - Interpretationown data
The thermogenic central actions of BMP8B are independent of environmental temperature.
“The Thermogenic Effect of Central BMP8B Is Independent of Environmental Temperature”
Quote in the paperNot a substantial claim - Study design and conductown data
Administration of AMPKα-CA adenoviruses alone did not have any impact on body temperature change or BAT temperature.
“The administration of AMPKα-CA adenoviruses alone did not have any impact either in body temperature change (vehicle GFP: 0.37°C ± 0.14°C versus vehicle AMPKα-CA: 0.3°C ± 0.11°C, non-significant) or BAT temperature (vehicle GFP: 0.35°C ± 0.21°C versus vehicle AMPKα-CA: 0.29°C ± 0.15°C, non-significant).”
Quote in the paperSubstantial claim - Interpretationown data
The effects of BMP8B on browning are specific for the VMH.
“Overall, these data indicated that the effects of BMP8B on browning are specific for the VMH.”
Quote in the paperSubstantial claim - Interpretationown data
OX acts downstream of AMPK in the VMH.
“Again, these data reinforced the ideas that the VMH-LHA circuit is essential for the central actions of BMP8B on BAT and that OX acts downstream of AMPK in the VMH.”
Quote in the paperSubstantial claim - Interpretationown data
AMPK in the VMH operates upstream of OX1R signaling in this pathway.
“suggesting that AMPK in that nucleus operates upstream of OX1R signaling in this pathway.”
Quote in the paperSubstantial claim - Interpretationown data
AMPK in the VMH is upstream of OX in the LHA.
“suggesting again that AMPK in the VMH is upstream of OX in the LHA.”
Quote in the paperSubstantial claim - Interpretationown data
The VMH-LHA circuit is essential for the central actions of BMP8B on BAT.
“Again, these data reinforced the ideas that the VMH-LHA circuit is essential for the central actions of BMP8B on BAT and that OX acts downstream of AMPK in the VMH.”
Quote in the paperSubstantial claim - Interpretationown data
Glutamatergic signaling acts downstream of AMPK.
“indicating that glutamatergic signaling was acting downstream of AMPK.”
Quote in the paperSubstantial claim - Interpretationown data
None of the outcomes was observed when BMP8B was specifically delivered into the LHA, which excluded its direct effect at this level.
“None of these outcomes was observed when BMP8B was specifically delivered into the LHA, which excluded its direct effect at this level.”
Quote in the paperSubstantial claim - Interpretationcitation
The projection of SF1 neurons from the VMH to the LHA may provide an anatomical basis for the interaction of AMPK(VMH)-glutamate-OX(LHA).
“which may provide an anatomical basis for the interaction of AMPK(VMH)-glutamate-OX(LHA).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lindberg et al., 2013 source
Not checked in the free run.
- Interpretationown data
AMPK in the VMH was acting upstream of OX neurons in the LHA.
“indicating that AMPK in the VMH was acting upstream of OX neurons in the LHA.”
Quote in the paperSubstantial claim - Premisecitation
VGLUT2 is highly expressed in the hypothalamus, including OX neurons.
“It is known that glutamate transporters, particularity VGLUT2, are highly expressed in the hypothalamus, including OX neurons (Ziegler et al., 2002, Rosin et al., 2003)”
Quote in the paperSubstantial claim0 of 2 sources checked - Study design and conductown data
Initial body weights did not differ significantly between vehicle and BMP8B groups in the VMH or LHA.
“initial body weight vehicle VMH: 240.0 ± 4.4 g versus BMP8B VMH: 237.5 ± 4.0 g; non-significant”
- Also stated in: § BMP8B in the VMH, but Not in the LHA, Induces Negative Energy Balance · plain
“initial body weight vehicle LHA: 233.0 ± 3.1 g versus BMP8B LHA: 235.1 ± 1.8 g; non-significant”
Quote in the paperNot a substantial claim - Also stated in: § BMP8B in the VMH, but Not in the LHA, Induces Negative Energy Balance · plain
- Interpretationown data
The data uncover a central network controlling energy homeostasis.
“Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders.”
Quote in the paperSubstantial claim - Interpretationreasoning
There is a functional link between AMPK in the VMH and OX neurons in the LHA.
“Here, we report a functional link between AMPK in the VMH and OX neurons in the LHA.”
Quote in the paperSubstantial claim - Premisecitation
SF1 neurons, a major cell population inside the VMH, project and terminate in the LHA.
“it has been revealed recently, by using conditional viral tracing, that SF1 neurons, a major cell population inside the VMH, project and terminate in the LHA (Lindberg et al., 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lindberg et al., 2013 source
Not checked in the free run.
- Interpretationcitation
BMP8B in the VMH recapitulated the effect of its central i.c.v. administration.
“Our data showed that administration of BMP8B within the VMH recapitulated the effect of its central (i.c.v.) administration (Whittle et al., 2012), namely feeding-independent weight loss, increased EE and BAT thermogenesis, and reduced RQ, in association with reduced AMPK signaling in the VMH and elevated BAT UCP1 protein content as well as browning of WAT.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whittle et al., 2012 source
Not checked in the free run.
- Interpretationown data
The VMH (AMPK), glutamate and LHA (OX) pathway provides the molecular basis for the interplay and balance between the VMH and LHA in the dynamic control of energy expenditure.
“but this VMH (AMPK), glutamate and LHA (OX) pathway provides the molecular basis for the interplay and balance between these two major areas in the dynamic control of other key aspect of the energy balance equation, namely EE.”
Quote in the paperSubstantial claim - Interpretationown data
Two important brain mediators of BAT thermogenesis act in a coordinate network.
“Our results show that two important brain mediators of BAT thermogenesis act in a coordinate network.”
Quote in the paperSubstantial claim - Interpretationown data
There is a functional connection among AMPK in the VMH, glutamatergic signaling, and OX in the LHA.
“and it uncovers a functional connection among AMPK in the VMH, glutamatergic signaling, and OX in the LHA.”
Quote in the paperSubstantial claim - Interpretationown data
The results uncover a physiological hypothalamic network governing energy homeostasis.
“First, they uncover a physiological hypothalamic network governing energy homeostasis, which might be of relevance for therapeutic approaches.”
Quote in the paperSubstantial claim - Interpretationown data
BMP8B modulates energy homeostasis and thermogenesis via a well-defined hypothalamic pathway involving a VMH-LHA interplay.
“this study demonstrates that BMP8B modulates energy homeostasis and, more precisely, thermogenesis, via a well-defined hypothalamic pathway involving a VMH-LHA interplay”
Quote in the paperSubstantial claim
- May combine two claims. 9
- Classified as probably not a substantial claim. 5
May combine two claims.
Findingown dataBMP8B in the LHA does not increase EE or reduce RQ.
“Moreover, BMP8B in the VMH, but not in the LHA, increased EE (Figures 2G and 2H) and reduced the respiratory quotient (RQ; Figures 2I and 2J).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSB-334867 significantly blunted the thermogenic effect of BMP8B at 4 and 6 hr after BMP8B treatment but only partially at 2 hr.
“However, SB-334867 significantly blunted the thermogenic effect of BMP8B at 4 and 6 hr after BMP8B treatment but only partially at 2 hr (Figure 4F), probably due to early effects independent of OX1R or a delayed effect of the antagonist.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBMP8B's impact on OX expression and thermogenesis is abolished by knockdown of VGLUT2, implicating glutamatergic signaling.
“its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling.”
Quote in the paperSubstantial claim- Rests on an assumption: The shVGLUT2 lentiviruses specifically reduce VGLUT2 in the LHA without off-target effects.
May combine two claims.
Findingown dataBoth the thermogenic effect of BMP8B and the elevation of OX mRNA expression were totally absent when BMP8B was given in combination with adenoviral particles encoding AMPKα-CA.
“We observed that both the thermogenic effect of BMP8B and the elevation of OX mRNA expression were totally absent when BMP8B was given in combination with adenoviral particles encoding AMPKα-CA, indicating that AMPK in the VMH was acting upstream of OX neurons in the LHA.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAMPK in the VMH and OX in the LHA modulate BAT thermogenesis.
“AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationBMP7 and BMP8B regulate BAT thermogenic function and increase EE.
“Thus, BMP7 and BMP8B were demonstrated to regulate BAT thermogenic function and increase EE (Tseng et al., 2008, Townsend et al., 2012, Townsend et al., 2013, Whittle et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationOX neurons in the LHA are required for BAT development and differentiation.
“In addition, OX neurons in the LHA are required for BAT development and differentiation (Sellayah et al., 2011, Sellayah and Sikder, 2012, Sellayah and Sikder, 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Sellayah et al., 2011 source
Not checked in the free run.
- cites Sellayah and Sikder, 2012
Not checked in the free run.
- cites Sellayah and Sikder, 2014
Not checked in the free run.
May combine two claims.
Interpretationown dataThe thermogenic effect of BMP8B is mediated by the inhibition of AMPK in the VMH, the glutamatergic signaling in the LHA, and the subsequent increase in OX signaling through OX1R.
“Moreover, we show that the thermogenic effect of BMP8B is mediated by the inhibition of AMPK in the VMH, the glutamatergic signaling in the LHA, and the subsequent increase in OX signaling through OX1R.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe correct position of the cannulae was verified by histological examination.
“The correct position of the cannulae was verified by histological examination of coronal sections of the brains (Figures S1A and S1B).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe above effects were reversed by pharmacological blockage of OX1R and were totally absent when BMP8B was centrally delivered in OX KO mice, even in a cold environment, which confirmed again AMPK's upstream position in this network.
“Importantly, the above effects were reversed by pharmacological blockage of OX1R and were totally absent when BMP8B was centrally delivered in OX KO mice, even in a cold environment, which confirmed again AMPK’s upstream position in this network.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataOVX rats gained significantly more weight and developed marked hyperphagia, confirming the efficiency of the OVX procedure.
“OVX rats gained significantly more weight (sham: 23.1 ± 2.38 g versus OVX: 71.3 ± 28 g; p < 0.001) and developed a marked hyperphagia (sham: 14.87 ± 0.31 g/day versus OVX: 17.70 ± 0.49 g/day; p < 0.01), confirming the efficiency of the OVX procedure.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataInfection efficiency was assessed by decreased VGLUT2 levels in the LHA.
“Infection efficiency was assessed by decreased VGLUT2 levels in that area (Figure 7A).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationVGLUT2 plays a main role in the regulation of energy balance.
“and play a main role in the regulation of energy balance (Tong et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tong et al., 2007 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataInfection efficiency was assessed by the expression of GFP in the VMH.
“Infection efficiency was assessed by the expression of GFP in the VMH (Figure 4B).”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Changes in phosphorylated AMPKα levels reflect changes in AMPK activity in the VMH.
“We found that VMH administration of BMP8B decreased the phosphorylated levels of AMPKα (pAMPKα) and its downstream target acetyl-CoA carboxylase alpha (pACCα); no changes were found in total levels of AMPKα1, AMPKα2, ACCα, and fatty acid synthase (FAS) (Figure 3A).”
The paper relies on this without support.
The shVGLUT2 lentiviruses specifically reduce VGLUT2 in the LHA without off-target effects.
“Infection efficiency was assessed by decreased VGLUT2 levels in that area (Figure 7A).”
The paper relies on this without support.
The OVX model with E2 replacement restores physiological estradiol levels.
“Of note, OVX rats with E2 replacement responded normally to BMP8B (Figures 1C and 1D).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hypothalamic expression of BMP8b in the VMH stimulates orexin secretion in the LHA through a decrease in AMPK activity and thus enhances firing of projections that stimulate BAT thermogenesis.
“Hypothalamic expression of bone morphogenetic protein 8b (BMP8b) in the VMH stimulates orexin secretion in the LHA through a decrease in AMPK activity and thus enhances the firing of projections that will stimulate BAT thermogenesis 79.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [79]
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References 73 · Cited by 154
- Authors
- Martins, L., Seoane-Collazo, P., Contreras, C., González-García, I., Martínez-Sánchez, N., González, F., Zalvide, J., Gallego, R., Diéguez, C., Nogueiras, R., Tena-Sempere, M., & López, M.
- Affiliations
- Universidade de Santiago de Compostela (ES)
- Corresponding author
- López, Miguel
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 16
- Issue
- 8
- Pages
- 2231-2242
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4999418
- OpenAlex
- W2515318044
- Semantic Scholar
- 1cc84e120c28559baaa6caf2291a06b9106d02da
- Cited by
- 154
- References
- 73
- Citations by year
- 2026: 33 · 2025: 5 · 2024: 11 · 2023: 9 · 2022: 16 · 2021: 12 · 2020: 12 · 2019: 20 · 2018: 17 · 2017: 15 · 2016: 4
- FWCI
- 11.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Hispana (submittedVersion, cc-by-nc-nd)
- Repositorio institucional da Universidade de Santiago de Compostela (University of Santiago de Compostela) (submittedVersion, other-oa)
- Funders
- Xunta de Galicia (PIE13/00024,, 2015-CP080, 2015-CP079)
- Instituto de Salud Carlos III (PIE13/00024, FP7/2007-2013, P12-FQM-01943)
- FP7 Ideas: European Research Council (281854)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- AMPK, orexin, BMP8B, brown adipose tissue thermogenesis, white adipose tissue browning, ventromedial hypothalamus, lateral hypothalamus, OX1 receptor, glutamatergic signaling, VGLUT2, energy homeostasis, obesity, sexual dimorphism
- MeSH terms
- Orexins, Animals, Body Weight, Adipose Tissue, Brown, Energy Metabolism, Female, Gene Expression Regulation, Hypothalamic Area, Lateral, Male, Sex Factors, Ventromedial Hypothalamic Nucleus, Signal Transduction, Rats, Sprague-Dawley, Mice, Knockout, Glutamic Acid, Bone Morphogenetic Proteins, Thermogenesis, Vesicular Glutamate Transport Protein 2, Rats, Adipose Tissue, White, AMP-Activated Protein Kinases, Orexin Receptors
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