A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance

Martins, Luís; Seoane-Collazo, Patricia; Contreras, Cristina; González-García, Ismael; Martínez-Sánchez, Noelia; González, Francisco; Zalvide, Juan; Gallego, Rosalı́a; Diéguez, Carlos; Nogueiras, Rubén; Tena‐Sempere, Manuel; López, Miguel

doi:10.1016/j.celrep.2016.07.045

Cited by 112 publications

(209 citation statements)

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“…Mice were not under anaesthesia and no special preparation was needed before the measurements. Mice were placed in a holder of custom-defined size during the measurement (measuring time ranged between 0.5 and 3.2 min)323334.…”

Section: Methodsmentioning

confidence: 99%

“…This system is an open-circuit instrument that determines O 2 consumption, CO 2 production and respiratory quotient (vCO 2 /vO 2 )323334. Mice were acclimated for 1 week before starting the measurements.…”

Section: Methodsmentioning

confidence: 99%

“…The protein concentration was determined by the Bradford method. Protein lysates were subjected to SDS–polyacrylamide gel electrophoresis, electrotransferred on a polyvinylidene difluoride membrane and probed with the following antibodies: UCP1 (1:10,000, Abcam, #ab10983) and α-tubulin (1:5,000, Sigma, T5168)323334. Then, the membrane was incubated with the corresponding secondary antibody: anti-mouse or anti-rabbit (all of them from DAKO, Denmark A/S).…”

Section: Methodsmentioning

confidence: 99%

“…The protein concentration was determined by the Bradford Method, and the total protein content of the tissues was calculated323334.…”

Section: Methodsmentioning

confidence: 99%

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A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

et al. 2017

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Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood–brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood–brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The protein concentration was determined by the Bradford Method, and the total protein content of the tissues was calculated323334.…”

Section: Methodsmentioning

confidence: 99%

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A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

et al. 2017

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“…Previous studies have identified higher levels of BMP8 expression as a molecular mechanism of estrogen-induced upregulation of metabolic activity in classic BAT of female mice [36]. Interestingly, recent studies demonstrated that thermogenic/browning effect of central BMP8b and AMPK activation in hypothalamus is restricted to female, showing estrogen dependency [34, 37, 38]. Further studies are needed to address whether the central regulation is involved in sex-dimorphic browning of gWAT.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in sympathetic innervation and browning of white adipose tissue of mice

et al. 2016

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BackgroundThe higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in β3-adrenergic remodeling of WAT in mice.MethodsEffects of the β3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15 days.ResultsWe found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate.ConclusionsCollectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen-dependent sympathetic innervation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0121-7) contains supplementary material, which is available to authorized users.

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Activation of Hypothalamic AMP‐Activated Protein Kinase Ameliorates Metabolic Complications of Experimental Arthritis

Seoane-Collazo

Rial-Pensado

Estévez-Salguero

et al. 2021

Arthritis & Rheumatology

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Objective. To investigate whether thermogenesis and the hypothalamus may be involved in the physiopathology of experimental arthritis (EA).Methods. EA was induced in male Lewis rats by intradermal injection of Freund's complete adjuvant (CFA). Food intake, body weight, plasma cytokines, thermographic analysis, gene and protein expression of thermogenic markers in brown adipose tissue (BAT) and white adipose tissue (WAT), and hypothalamic AMP-activated protein kinase (AMPK) were analyzed. Virogenetic activation of hypothalamic AMPK was performed.Results. We first demonstrated that EA was associated with increased BAT thermogenesis and browning of subcutaneous WAT leading to elevated energy expenditure. Moreover, rats experiencing EA showed inhibition of hypothalamic AMPK, a canonical energy sensor modulating energy homeostasis at the central level. Notably, specific genetic activation of AMPK in the ventromedial nucleus of the hypothalamus (a key site modulating energy metabolism) reversed the effect of EA on energy balance, brown fat, and browning, as well as promoting amelioration of synovial inflammation in experimental arthritis.Conclusion. Overall, these data indicate that EA promotes a central catabolic state that can be targeted and reversed by the activation of hypothalamic AMPK. This might provide new therapeutic alternatives to treat rheumatoid arthritis (RA)-associated metabolic comorbidities, improving the overall prognosis in patients with RA.

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A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance

Cited by 112 publications

References 74 publications

A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

Sex differences in sympathetic innervation and browning of white adipose tissue of mice

Activation of Hypothalamic AMP‐Activated Protein Kinase Ameliorates Metabolic Complications of Experimental Arthritis

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