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Gpbar1 agonism promotes a Pgc-1?-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice.

ABSTRACT: Gpbar1 is a bile acid activated receptor for secondary bile acids. Here we have investigated the mechanistic role of Gpbar1 in the regulation of adipose tissues functionality in a murine model of steatohepatitis (NASH). Feeding wild type and Gpbar1-/- mice with a high fat diet-fructose (HFD-F) lead to development of NASH-like features. Treating HFD-F mice with 6?-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol (BAR501), a selective Gpbar1-ligand, reversed insulin resistance and histologic features of NASH, increased the weight of epWAT and BAT functionality and promoted energy expenditure and the browning of epWAT as assessed by measuring expression of Ucp1 and Pgc-1?. The beneficial effects of BAR501 were lost in Gpbar1-/- mice. In vitro, BAR501 promoted the browning of 3T3-L1 cells a pre-adipocyte cell line and recruitment of CREB to the promoter of Pgc-1?. In conclusion, Gpbar1 agonism ameliorates liver histology in a rodent model of NASH and promotes the browning of white adipose tissue.

SUBMITTER: Carino A

PROVIDER: S-EPMC5651899 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Gpbar1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice.

Carino Adriana A Cipriani Sabrina S Marchianò Silvia S Biagioli Michele M Scarpelli Paolo P Zampella Angela A Monti Maria Chiara MC Fiorucci Stefano S

Scientific reports 20171020 1

Gpbar1 is a bile acid activated receptor for secondary bile acids. Here we have investigated the mechanistic role of Gpbar1 in the regulation of adipose tissues functionality in a murine model of steatohepatitis (NASH). Feeding wild type and Gpbar1<sup>-/-</sup> mice with a high fat diet-fructose (HFD-F) lead to development of NASH-like features. Treating HFD-F mice with 6β-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol (BAR501), a selective Gpbar1-ligand, reversed insulin resistance and histologic featu ...[more]

PMID: 29057935

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Project description:Objective: Increasing the mass and/or activity of brown adipose tissue (BAT) is one promising avenue for treating obesity and related metabolic conditions, given that BAT has a high potential for energy expenditure and is capable of improving glucose and lipid homeostasis. BAT occurs either in discrete “classical” depots, or interspersed in white adipose tissue (WAT), termed “inducible/recruitable” BAT, or ‘beige/brite’ adipocytes. We and others have demonstrated that bone morphogenetic protein 7 (BMP7) induces brown adipogenesis in committed and uncommitted progenitor cells, resulting in increased energy expenditure and reduced weight gain in mice. BMP7 is therefore a reliable growth factor to induce browning of WAT. Methods: In this study, we sought to deliver BMP7 specifically to subcutaneous (sc)WAT in order to induce tissue-resident progenitor cells to differentiate into energy-expending recruitable brown adipocytes, without off-target effects like bone formation, which can occur when BMPs are in the presence of bone progenitor cells (outside of WAT). BMP7 delivery directly to WAT may also promote tissue innervation, or directly activate mitochondrial activity in brown adipocytes, as we have demonstrated previously. We utilized silk protein in the form of an injectable hydrogel carrying BMP7. Silk scaffolds are useful for in vivo delivery of substances due to favorable material properties, including controlled release of therapeutic proteins in an active form, biocompatibility with minimal immunogenic response, and prior FDA approval for some medical materials. For this study, the silk was engineered to meet desirable release kinetics for BMP7 in order to mimic our prior in vitro brown adipocyte differentiation studies. Fluorescently-labeled silk hydrogel loaded with BMP7 was directly injected into WAT through the skin and monitored by non-invasive in vivo whole body imaging, including in UCP1-luciferase reporter mice, thereby enabling an approach that is translatable to humans. Results: Injection of the BMP7-loaded silk hydrogels into the subcutaneous WAT of mice resulted in “browning”, including the development of multilocular, uncoupling protein 1 (UCP1)-positive brown adipocytes, and an increase in whole-body energy expenditure and skin temperature. In diet-induced obese mice, BMP7-loaded silk delivery to subcutaneous WAT resulted in less weight gain, reduced circulating glucose and lower respiratory exchange ratio (RER). Conclusions: In summary, BMP7 delivery via silk scaffolds directly into scWAT is a novel translational approach to increase browning and energy expenditure, and represents a potential therapeutic avenue for delivering substances directly to adipose depots in pursuit of metabolic treatments.

Project description:BackgroundTrehalose is well known as a functional disaccharide with anti-metabolic activities such as suppression of adipocyte hypertrophy in mice and alleviation of impaired glucose tolerance in humans. Recently, a new type of adipocyte beige cells, involved in so-called white adipocyte tissue (WAT) browning, has received much attention as a target for adaptive thermogenesis. To clarify the relationship between adipocyte hypertrophy suppression and beige cells involved in thermogenesis, we examined the effect of trehalose on the changes in beige adipocytes in mice under normal dietary conditions.MethodsMice fed a normal diet were administered water containing 0.3% (W/V) trehalose for 16 weeks, 0.3% (W/V) maltose, or water without saccharide (controls). Body temperature and non-fasting blood glucose levels were measured every 3 weeks. After 16 weeks of these treatments, mesenteric and inguinal adipose tissues were collected for measuring adipocyte size, counting the number of UCP1 positive cells by image analysis, and preparing mRNA to analyze beige adipocyte-related gene expression.ResultsMice administered a continuous intake of trehalose exhibited a thermogenic ability as represented by an increase in rectal temperature, which was maintained at a relatively high level from 3 to 9 weeks and was significantly higher at 15 weeks in comparison with that of the maltose group. In addition to the reduced hypertrophy of mesenteric and inguinal adipose tissues, the trehalose group showed a significant increase in the rates of beige adipocytes in each WAT in comparison with those of the maltose and the water groups. Interestingly, a negative correlation was found between the mean cell sizes of adipocytes and the rates of beige adipocytes in the WAT. Furthermore, real-time PCR showed that the expression of Cidea and Ucp1 mRNAs, which are markers for beige adipocytes in the inguinal adipose tissue, increased in the trehalose group.ConclusionsContinuous administration of trehalose to mice fed a normal diet induced WAT browning accompanied by suppression of white adipocyte hypertrophy, elevated body temperature and decreased blood glucose levels, which resulted in enhancement of energy metabolism. Therefore, we propose trehalose as a new type of thermogenic dietary component to prevent obesity by promoting WAT browning.

Dataset Information

Gpbar1 agonism promotes a Pgc-1?-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice.

Publications

Gpbar1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice.

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