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Calorie restriction (CR) and exercise training (EX) are two critical lifestyle interventions for the prevention and treatment of metabolic diseases, such as obesity and diabetes. Brown adipose tissue (BAT) and skeletal muscle are two important organs for the generation of heat. Here, we undertook detailed transcriptional profiling of these two thermogenic tissues from mice treated subjected to CR and/or EX. We found transcriptional reprogramming of BAT and skeletal muscle as a result of CR but little from EX. Consistent with this, CR induced alterations in the expression of genes encoding adipokines and myokines in BAT and skeletal muscle, respectively. Deconvolution analysis showed differences in the subpopulations of myogenic cells, mesothelial cells and endogenic cells in BAT and in the subpopulations of satellite cells, immune cells and endothelial cells in skeletal muscle as a result of CR or EX. NicheNet analysis, exploring potential inter-organ communication, indicated that BAT and skeletal muscle could mutually regulate their fatty acid metabolism and thermogenesis through ligands and receptors. These data comprise an extensive resource for the study of thermogenic tissue molecular responses to CR and/or EX in a healthy state.

Obesity is the result of excessive energy accumulation and is associated with many diseases. We previously reported that universal repression of vascular endothelial growth factor (VEGF) leads to brown-like adipocyte development in white adipose tissues, and that these mice are resistant to obesity (Lu X et al. Endocrinology 153: 3123-3132, 2012). Using an adipose-specific VEGF repression mouse model (aP2-rtTR-krab tg/+ /VEGF tetO/tetO ), we show that adipose-specific VEGF repression can repeat the previous phenotypes, including adipose browning, increased energy consumption, and reduction in body weight. Expression of brown adipose-associated genes is increased, and white adipose-associated genes are downregulated under VEGF repression. Our study demonstrates that adipose-specific VEGF repression can lead to antiobesity activity through adipose browning and has potential clinical value.

Obesity is the result of abnormal adipose development and energy metabolism. Using vascular endothelial growth factor (VEGF) B-knockout and inducible VEGF downregulation mouse models, we have shown that VEGFB inactivation caused expansion of white adipose, whitening of brown adipose, an increase in fat accumulation, and a reduction in energy consumption. At the same time, expression of the white adipose-associated genes was increased and brown adipose-associated genes decreased. VEGF repression, in contrast, induced brown adipose expansion and brown adipocyte development in white adipose, increased energy expenditure, upregulated brown adipose-associated genes, and downregulated white adipose-associated genes. When VEGFB-knockout and VEGF-repressed mice are crossed together, VEGF and VEGFB can counteractively regulate large numbers of genes and efficiently reverse each other's roles. These genes, under counteractive VEGF and VEGFB regulations, include transcription factors, adhesion molecules, and metabolic enzymes. This balancing role is confirmed by morphologic and functional changes. This study reports that VEGF and VEGFB counteractively regulate adipose development and function in energy metabolism.

Adipose tissues are classified into white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is responsible for energy storage, and malfunction is associated with obesity. BAT, on the contrary, consumes fat to generate heat through uncoupling mitochondrial respiration and is important in body weight control. Vascular endothelial growth factor (VEGF)-A is the founding member of the VEGF family and has been found highly expressed in adipose tissue. A genetic mouse model of an inducible VEGF (VEGF-A) repression system was used to study VEGF-regulated energy metabolism in WAT. VEGF-repressed mice demonstrated lower food efficiency, lower body weight, and resistance to high-fat diet-induced obesity. Repression of VEGF expression caused morphological and molecular changes in adipose tissues. VEGF repression induced brown-like adipocyte development in WAT, up-regulation of BAT-specific genes including PRDM16, GATA-1, BMP-7, CIDEA, and UCP-1 and down-regulation of leptin, a WAT-specific gene. VEGF repression up-regulated expression of VEGF-B and its downstream fatty acid transport proteins. Relative levels of VEGF/VEGF-B may be important switches in energy metabolism and of pharmaceutical significances.