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Coordinate control of adipose 'browning' and energy expenditure by β-adrenergic and natriuretic peptide signalling.

ABSTRACT: The catecholamines and the adrenergic receptors have been long known to be vital components in the regulation of fat cell metabolism. Whether in response to stress, cold temperature or diet, the β-adrenergic receptors (βARs) respond to epinephrine/norepinephrine to activate a signalling cascade that drives triglyceride hydrolysis to free fatty acids for use as fuel for skeletal and cardiac muscle work. The βARs also are well-established activators of brown fat for the conversion of substrate energy to generate heat from the oxidation of glucose and fatty acids. Long thought to be irrelevant to the biology of adult humans, the realization that there is indeed functional brown fat in humans has now created great interest and enthusiasm over the possibility that recruiting brown fat to target obesity and metabolic disease could represent a viable therapeutic option. Coupled with newer evidence that various stimuli independent of the βARs may also be able to increase active brown adipocytes, including the cardiac natriuretic peptides, it is an exciting time to be working in this area. This review will focus on the catecholamines and natriuretic peptides as cooperative actors in promoting fat metabolism, and will consider areas in need of further research.

SUBMITTER: Collins S

PROVIDER: S-EPMC4850585 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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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.

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Coordinate control of adipose 'browning' and energy expenditure by β-adrenergic and natriuretic peptide signalling.

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