Role of cAMP and cGMP Signaling in Brown Fat.

Cold-induced activation of brown adipose tissue (BAT) is mediated by norepinephrine and adenosine that are released during sympathetic nerve activation. Both signaling molecules induce an increase in intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) in murine and human BAT. In brown adipocytes, cAMP plays a central role, because it activates lipolysis, glucose uptake, and thermogenesis. Another well-studied intracellular second messenger is 3',5'-cyclic guanosine monophosphate (cGMP), which closely resembles cAMP. Several studies have shown that intact cGMP signaling is essential for normal adipogenic differentiation and BAT-mediated thermogenesis in mice. This chapter highlights recent observations, demonstrating the physiological significance of cyclic nucleotide signaling in BAT as well as their potential to induce browning of white adipose tissue (WAT) in mice and humans.

Impact of obesity and aging on crestal alveolar bone height in mice.

Obesity and aging are associated with periodontitis, which represents a chronic inflammatory disease of the tooth-supporting tissues, i.e. the periodontium. However, if both risk factors also have a negative impact on crestal alveolar bone in a clinically healthy periodontium, has yet to be elucidated and was analyzed in this in-vivo study. Eight C57BL/6 mice were fed a normal diet during the entire study. Half of these mice were sacrificed at week 19 (group 1: younger lean mice), whereas the other half of the animals were sacrificed at week 25 (group 2: older lean mice). In addition, four mice were fed a high-fat diet until their sacrifice at week 19 (group 3: younger obese mice). Mandibles and maxillae were scanned by micro-computed tomography and, subsequently, the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) at all molars was determined. Levels of interleukin-6, cyclooxygenase-2, visfatin and adiponectin in gingival samples were quantified by real-time PCR. For statistical analyses, the Mann-Whitney-U test was applied (p<0.05). As compared to lean mice, obese animals presented a significantly increased CEJ-ABC distance, i.e. reduced alveolar bone crest height, at week 19. The alveolar bone loss was mainly found at the first molars of the mandibles. In animals fed a normal diet, the alveolar bone crest height in the mandibles and maxillae was significantly lower in the older mice as compared to the younger animals. Furthermore, gingival cyclooxygenase-2 and visfatin expressions were higher in the obese versus lean mice and in the older versus younger mice. This in-vivo investigation shows that obesity and older age can result in reduced alveolar bone crest height and suggests that they represent risk factors even in a clinically healthy periodontium.

Interplay between Obesity-Induced Inflammation and cGMP Signaling in White Adipose Tissue.

Current worldwide figures suggest that obesity is pandemic. Understanding the underlying molecular mechanisms would help develop viable anti-obesity therapies. Here, we assess the influence of obesity-induced inflammation on white adipocyte cyclic guanosine monophosphate (cGMP) signaling, which is beneficial for adipocyte differentiation and thermogenesis. We find that murine gonadal and not inguinal fat is prone to obesity-induced inflammation. Correspondingly, the cGMP cascade is dysregulated in gonadal but not in inguinal fat of obese mice. Analysis of two independent human cohorts reveals a defective cGMP pathway only in visceral fat of obese subjects. Congruently, cGMP signaling is dysregulated in tumor necrosis factor α (TNF-α)-treated primary white adipocytes. TNF-α-mediated suppression of sGCß1 is mediated via NF-κB, whereas PKG is repressed by JNK signaling. Additionally, TNF-α-activated JNK signaling suppresses PPARγ and aP2. Taken together, the intensity of obesity-induced inflammation dictates the amplitude of cGMP signaling dysregulation in white adipocytes through distinct pathways.

Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue.

Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing ß1-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.