The results of our study show that pharmacological sGC stimulation protects against DIO and induces weight loss in already established obesity. The changes in body weight induced by the sGC stimulator are accompanied by improved overall metabolic status as indicated by improved glucose tolerance, decreased liver steatosis, reduced insulin levels and decreased adipocyte size in WATi, a parameter for healthy expansion of WAT36. Importantly, EE was increased under basal conditions and we found significantly increased lipid uptake into BAT. Previously, it has been shown that active BAT can take up ∼50% of nutrient lipids30,37 resulting in increased EE19,38. Moreover, also muscle and WAT tended to take up more lipids after treatment with the sGC stimulator and, therefore, could contribute to the increase in EE.

In this context, it is of interest that EE was increased during exercise after sGC stimulation and that mitochondrial biogenesis was increased in muscle of BAY-treated mice. Similar results were observed in a genetic model of increased downstream cGMP signalling where mitochondrial biogenesis and EE were increased in mice overexpressing the cGMP-target PKGI34. These data indicate that sGC stimulators might be used to enhance weight loss induced by physical activity.

Mice treated with the sGC stimulator showed ‘browning’ of WAT, that is, the appearance of inducible BA in WAT, which is in line with previous studies23,25 that have shown cGMP-dependent browning of WAT. In addition, we found that HFD-induced ‘whitening’ of classical, interscapular BAT was reduced on sGC stimulation. Thus, sGC stimulation recruits BAT and increases EE with increased uptake of lipids especially into BAT. Our data might also extend to humans as sGC stimulation induced thermogenic markers in human WA and BA.

The downstream cGMP pathway is an important regulator of BAT that mediates the effects of BAY and has been deciphered earlier9. It consists of the cGMP-producing enzymes sGC and particulate guanylyl cyclases (NPR-A and NPR-B). PGKI, the major downstream target of sGC, is indispensible for thermogenic differentiation of BA in vitro and in vivo and is crucially involved in browning of WAT20,23. PKGI inhibits RhoA that results in the release of the RhoA/ROCK-dependent inhibition of the insulin/IRS-1/PI3K/Akt pathway. In the activated state, the cGMP pathway results in mitochondrial biogenesis and induction of UCP1 (refs 20, 21). On the other hand, phosphodiesterases (PDEs) reduce the levels of cGMP in adipocytes39 and inhibition of PDE5 results in browning23.

Here we focused on sGC as a new target in antiobesity therapy to modulate cGMP signalling at the level of cGMP production. Mice lacking the β 1 -subunit of sGC, which contains the haeme-binding domain that is critical for activation of sGC by NO and BAY40,41, show a severe phenotype with reduced BAT-derived thermogenesis and altered differentiation of BA. Thus, sGC is essential for normal differentiation of BAT.

This important signalling cascade can be regulated pharmacologically at several levels. Organic nitrates that deliver NO have been used to treat angina pectoris for more than 100 years42, and NO has been shown to be involved in mitochondrial biogenesis in a broad range of cells including BA21. Its volatile nature and primary action in the vasculature argue against a BAT-specific effect of NO in a possible therapeutic application of NO in obesity. Furthermore, nitrate tolerance43 is a major drawback that develops rapidly making long-term application not applicable, which would be necessary in antiobesity therapies.

Natriuretic peptides that activate NPR-A and NPR-B have been shown to increase thermogenic markers in human BA, are capable of increasing EE in mice with concomitant browning of WAT25 and have been shown to counteract DIO34. In light of the positive effects of natriuretic peptides on EE25, it is of special interest that ablation of sGCβ 1 has such a profound effect on BA differentiation and function demonstrating the central role of sGC-derived cGMP in BAT. Brain natriuretic peptide (BNP) has been used pharmacologically to treat acute decompensated heart failure; however, its safety has been questioned44,45 and the use of BNP might not be feasible in all obesity patients.

Another way to pharmacologically modulate cGMP signalling is the use of PDE5 inhibitors such as sildenafil, which leads to increased cGMP levels. Members of this drug class have been used mainly for the treatment of erectile dysfunction for several years46. In mice, short-term treatment with sildenafil results in browning of WAT23 and long-term treatment with sildenafil induced weight reduction in mice on HFD47. Important side effects of these drugs including interactions with agents that lower blood pressure such as nitrates48 or alpha blockers49 and an increased risk for development of melanoma50 have been reported.

Thus, alternative strategies for enhancing cGMP signalling in adipocytes at different levels of the cascade are required for rational therapy. Modulating signalling pathways at different levels has been proven to be a prerequisite for successful treatment of multilayered diseases in heterogeneous groups of patients. For example, the development of several pharmacological strategies to regulate the renin–angiotensin–aldosterone system resulted in different classes of drugs that can be administered to different subpopulations of patients with hypertension and renal disorders as well as cardiovascular disease and provide efficient alternative treatment options.

To increase sGC-dependent cGMP production, we used a member of the new drug class of sGC stimulators. These compounds stimulate the native sGC in a haeme-dependent manner and show a strong synergism with NO (ref. 29). These characteristics allow sGC stimulators to increase cGMP signalling even when endogenous NO/cGMP signalling is impaired because of reduced bioavailability of NO. The compound used in this study is chemically closely related to riociguat51, which is used for the treatment of pulmonary hypertension and shows a favourable safety profile52.

In the clinical trials with the sGC stimulator riociguat, the included patients had normal body weights52,53. Importantly, patients with obesity were excluded from the studies. Moreover, patients suffering from pulmonary hypertension rather tend to have a lower body because of their severe disease. A significant change in body weight of the patients who were included was not observed in the clinical trials with riociguat.

In the light of the results from the Collins laboratory, which show that natriuretic peptides increase EE and induce browning in animal models, the concept of natriuretic peptides as antiobesity drugs seems to be promising25. To our knowledge, an effect of administered natriuretic peptides on body weight in clinical trials has not been published so far. Clinical trials investigating the effects of natriuretic peptides on obesity are underway54.

In summary, pharmacological stimulation of sGC increases the function of BA and induces a brown, energy-combusting phenotype in WA. Importantly, sGC stimulation counteracts DIO-induced pathologies even in already established obesity via increased energy utilization. Activation of sGC results in increased lipid uptake and usage mainly by BAT. Overall, sGC stimulation leads to reduced body weight and an improved metabolic phenotype in mice with DIO. sGC stimulation represents an innovative pharmacological principle and sGC stimulators are potential candidates for the treatment of obesity and associated comorbidities.