Reduced adiposity and high-fat diet-induced adipose inflammation in mice deficient for phosphodiesterase 4B.
The concept that obesity is an inflammatory state has changed our understanding of this condition and suggested that pharmacological interventions targeting inflammation may be useful strategies to improve metabolic complications of obesity. Phosphodiesterase 4 (PDE4) inhibitors exhibit profound antiinflammatory effects, but whether PDE4 inhibition suppresses obesity-induced inflammation is unknown. Among PDE4 isoforms, PDE4B is the major species mediating inflammatory responses. We therefore examined obesity-related phenotypes in mice deficient for PDE4B. Compared with wild-type littermates, PDE4B-null mice were leaner, with lower fat pad weights, smaller adipocytes, and decreased serum leptin levels on both chow and high-fat diets (HFDs). PDE4B deficiency suppressed TNF-alpha mRNA levels and macrophage infiltration in white adipose tissue in mice on HFD, but insulin sensitivity was unaltered. PDE4B-null mice on HFDs had increased locomotor activity. These results suggest a previously unappreciated role for PDE4B in the regulation of energy balance and that PDE4B inhibitors could have utility in treatment of obesity and for suppression of obesity-induced inflammation in white adipose tissue.
Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
Ren
R
Zhang
Eleftheria
E
Maratos-Flier
Jeffrey S
JS
Flier
D017667:Adipocytes / Q000166:cytology; D052436:Adipose Tissue, White / Q000166:cytology* / Q000187:drug effects; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D048429:Cell Size; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000172:deficiency*; D004041:Dietary Fats / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D015434:Panniculitis / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004041:Dietary Fats; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4