Brown adipose tissue (BAT) is the most essential thermogenic organ in homeotherms. In mice, brown adipocytes like cells (beige adipocytes) appear in subcutaneous fat depot after prolonged cold exposure. Fully-functioning BAT and beige adipocytes in subcutaneous fat depot drive a sharp increase in energy expenditure. In fact, cold-elicited BAT activation and beige cell recruitment in subcutaneous adipose tissue have shown anti -obesity effect, making them a promising target for obesity treatment. Due to the practice reasons, intermittent cold exposure may be an effective approach to activate BAT and to treat obesity and type 2 diabetes. However, cold exposure is known to induce various physiological changes and therefore warrants a comprehensive study looking at the effects of cold exposure on the whole body energy homeostasis. We found that intermittent cold exposure (ICE) leads to mild adaptive hyperphagia and fat accumulation in mice. Fat accumulation was mostly observed in subcutaneous adipose tissue with increased lipogenesis genes expression. ICE also increased fat accumulation in liver. Interestingly, pair-feeding and restrain studies ruled out the causal role of hyperphagia and stress on ICE-induced fat accumulation. In conclusion, intermittent cold exposure shifts energy homeostasis favoring fat accumulation in mice, although ICE stimulates BAT activation and beige cell recruitment in inguinal fat

Aims/hypothesis

Adiponectin is an adipocyte-derived hormone that plays an important role in energy homeostasis. The main objective of this study was to investigate whether or not adiponectin regulates brown adipose tissue (BAT) activation and thermogenesis.

Methods

Core body temperatures (CBTs) of genetic mouse models were monitored at room temperature and during cold exposure. Cultured brown adipocytes and viral vector-mediated gene transduction were used to study the regulatory effects of adiponectin on Ucp1 gene expression and the underlying mechanisms.

Results

The CBTs of adiponectin knockout mice (Adipoq(-/-)) were significantly higher than those of wild type (WT) mice both at room temperature and during the cold (4°C) challenge. Conversely, reconstitution of adiponectin in Adipoq(-/-) mice significantly blunted β adrenergic receptor agonist-induced thermogenesis of interscapular BAT. After 10 days of intermittent cold exposure, Adipoq(-/-) mice exhibited higher UCP1 expression and more brown-like structure in inguinal fat than WT mice. Paradoxically, we found that the anti-thermogenic effect of adiponectin requires neither AdipoR1 nor AdipoR2, two well-known adiponectin receptors. In sharp contrast to the anti-thermogenic effects of adiponectin, AdipoR1 and especially AdipoR2 promote BAT activation. Mechanistically, adiponectin was found to inhibit Ucp1 gene expression by suppressing β3-adrenergic receptor expression in brown adipocytes.

Conclusions/interpretation

This study demonstrates that adiponectin suppresses thermogenesis, which is likely to be a mechanism whereby adiponectin reduces energy expenditure.

Due to its high energy consuming characteristics, brown adipose tissue (BAT) has been suggested as a key player in energy metabolism. Cold exposure is a physiological activator of BAT. Intermittent cold exposure (ICE), unlike persistent exposure, is clinically feasible. The main objective of this study was to investigate whether ICE reduces adiposity in C57BL/6 mice. Surprisingly, we found that ICE actually increased adiposity despite enhancing Ucp1 expression in BAT and inducing beige adipocytes in subcutaneous white adipose tissue. ICE did not alter basal systemic insulin sensitivity, but it increased liver triglyceride content and secretion rate as well as blood triglyceride levels. Gene profiling further demonstrated that ICE, despite suppressing lipogenic gene expression in white adipose tissue and liver during cold exposure, enhanced lipogenesis between the exposure periods. Together, our results indicate that despite enhancing BAT recruitment, ICE in mice increases fat accumulation by stimulating de novo lipogenesis.