Abstract
Understanding mechanisms by which a population of beige adipocytes is increased in white adipose tissue (WAT) reflects a potential strategy in the fight against obesity and diabetes. Cyclic adenosine monophosphate (cAMP) is very important in the development of the beige phenotype and activation of its thermogenic program. To study effects of cyclic nucleotides on energy homeostatic mechanisms, mice were generated by targeted inactivation of cyclic nucleotide phosphodiesterase 3b (Pde3b) gene, which encodes PDE3B, an enzyme that catalyzes hydrolysis of cAMP and cGMP and is highly expressed in tissues that regulate energy homeostasis, including adipose tissue, liver, and pancreas. In epididymal white adipose tissue (eWAT) of PDE3B KO mice on a SvJ129 background, cAMP/protein kinase A (PKA) and AMP-activated protein kinase (AMPK) signaling pathways are activated, resulting in “browning” phenotype, with a smaller increases in body weight under high-fat diet, smaller fat deposits, increased β-oxidation of fatty acids (FAO) and oxygen consumption. Results reported here suggest that PDE3B and/or its downstream signaling partners might be important regulators of energy metabolism in adipose tissue, and potential therapeutic targets for treating obesity, diabetes and their associated metabolic disorders.
Highlights
Obesity is a major risk factor for type 2 diabetes and cardiovascular disease
We show that targeted inactivation of the murine SvJ129 phosphodiesterase 3b (Pde3b) gene was associated with activation of Cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and AMPK signaling pathways, the integration of which resulted in “browning” of KO epididymal white adipose tissue (eWAT), with increased expression of genes and proteins related to mitochondrial biogenesis and function, thermogenesis, and energy dissipation, including PR domain containing 16 (PRDM16), leucine-rich protein 130 (LRP130), PGC-1α, SIRT3, uncoupling protein 1 (UCP1), ELOVL3, PPARα, and the enzymatic machinery for FAO
We previously reported that eWAT mass and adipocyte size were decreased in age-matched male KO mice compared to wild type (WT), body weight was increased in KO mice[31]
Summary
Obesity is a major risk factor for type 2 diabetes and cardiovascular disease. White adipose tissue (WAT), a highly regulated and dynamic secretory organ, affects body fat and energy utilization through storage and turnover/ hydrolysis of triglycerides. Induction/activation of BAT in rodents is associated with decreased adiposity, improved responsiveness to insulin, and reduced serum free fatty acids (FFA), i.e., a “lean” phenotype which may confer protection against diabetes, obesity, and their metabolic sequelae[6,7,8,9]. It is not essential for BAT differentiation, PPARγco-activator 1 alpha (PGC-1α) is a critical transcriptional activator of cAMP-mediated mitochondrial biogenesis and induction of the thermogenic program[10]. The coactivator function of PGC-1αin modulating gene expression seems to be regulated, in a feedback fashion, by leucine-rich protein 130 (LRP130), a PGC-1α-inducible factor[40]
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