Brown adipocytes are a primary site of energy expenditure and reside not only in classical brown adipose tissue but can also be found in white adipose tissue. Here we show that microRNA 155 is enriched in brown adipose tissue and is highly expressed in proliferating brown preadipocytes but declines after induction of differentiation. Interestingly, microRNA 155 and its target, the adipogenic transcription factor CCAAT/enhancer-binding protein β, form a bistable feedback loop integrating hormonal signals that regulate proliferation or differentiation. Inhibition of microRNA 155 enhances brown adipocyte differentiation and induces a brown adipocyte-like phenotype (‘browning’) in white adipocytes. Consequently, microRNA 155-deficient mice exhibit increased brown adipose tissue function and ‘browning’ of white fat tissue. In contrast, transgenic overexpression of microRNA 155 in mice causes a reduction of brown adipose tissue mass and impairment of brown adipose tissue function. These data demonstrate that the bistable loop involving microRNA 155 and CCAAT/enhancer-binding protein β regulates brown lineage commitment, thereby, controlling the development of brown and beige fat cells.

High malignancy and early metastasis are hallmarks of melanoma. Here, we report that the transcription factor Snail1 inhibits expression of the tumor suppressor CYLD in melanoma. As a direct consequence of CYLD repression, the protooncogene BCL-3 translocates into the nucleus and activates Cyclin D1 and N-cadherin promoters, resulting in proliferation and invasion of melanoma cells. Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo. Analysis of a tissue microarray with primary melanomas from patients revealed an inverse correlation of Snail1 induction and loss of CYLD expression. Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression. Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.

PKG regulates differentiation and thermogenic function in brown adipose tissue.

With more than half a billion individuals affected worldwide, obesity has reached pandemic proportions. Development of “brown‐like” or “brite” adipocytes within white adipose tissue (WAT) has potential antiobesity and insulin‐sensitizing effects. We investigated the role of cyclic GMP (cGMP) signaling, focusing on cGMP‐dependent protein kinase I (PKGI) in WAT. PKGI is expressed in murine WAT, primary adipocytes, and 3T3‐L1. Treatment of adipocytes with cGMP resulted in increased adipogenesis, with a 54% increase in expression of peroxisome proliferator‐activated receptor‐γ. Lentiviral overexpression of PKGI further increased adipogenesis, whereas loss of PKGI significantly reduced adipogenic differentiation. In addition to adipogenic effects, PKGI had an antihypertrophic and anti‐inflammatory effect via RhoA phosphorylation and reduction of proinflammatory adipokine expression. Moreover, PKGI induced a 4.3‐fold increase in abundance of UCP‐1 and the development of a brown‐like thermogenic program in primary adipocytes. Notably, treatment of C57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 d caused 4.6‐fold increase in uncoupling protein‐1 expression and promoted establishment of a brown fat cell‐like phenotype (“browning”) of WAT in vivo. Taken together, PKGI is a key regulator of cell size, adipokine secretion and browning of white fat depots and thus could be a valuable target in developing novel treatments for obesity.—Mitschke, M. M., Hoffmann, L. S., Gnad, T., Scholz, D., Kruithoff, K., Mayer, P., Haas, B., Sassmann, A., Alexander Pfeifer, A, Kilić, A. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27, 1621–1630 (2013). www.fasebj.org

Prevalence of diabetes mellitus is inc6reasing, with a burden of 382 million patients worldwide at present (more than the entire US population). The International Diabetes Federation anticipates an increase up to 592 million patients by 2035. Another major problem arises from the fact that just 50% of patients with type 2 diabetes mellitus are at target glycaemic control with currently available medications. Therefore, a clear need for new therapies that aim to optimize glycaemic control becomes evident. Renal sodium-linked glucose transporter 2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They pose one remarkable advantage compared with already established antidiabetics: increasing urinary glucose excretion without inducing hypoglycaemia, thereby promoting body weight reduction due to loss of ~300 kcal per day. This review focuses on canagliflozin, which was the first successful compound of this class to be approved by both the US Food and Drug Administration and the European Medicines Agency in 2013. Clinical trials showed promising results: enhancing glycaemic control was paralleled by reducing body weight and systolic and diastolic blood pressure. Nevertheless, some safety concerns remain, such as genital mycotic infections, urinary tract infections and cardiovascular risks in vulnerable patients, which will be closely monitored in several post-authorization safety studies.

Mechanical stimulation is crucial for bone growth and remodeling, and fluid shear stress promotes anabolic responses in osteoblasts through multiple second messengers, including nitric oxide (NO). NO triggers production of cyclic guanosine 3′,5′-monophosphate (cGMP), which in turn activates protein kinase G (PKG). We found that the NO-cGMP-PKG signaling pathway activates Src in mechanically stimulated osteoblasts to initiate a proliferative response. PKGII was necessary for Src activation, a process that also required the interaction of Src with β₃ integrins and dephosphorylation of Src by a complex containing the phosphatases SHP-1 (Src homology 2 domain–containing tyrosine phosphatase 1) and SHP-2. PKGII directly phosphorylated and stimulated SHP-1 activity, and fluid shear stress triggered the recruitment of PKGII, Src, SHP-1, and SHP-2 to a mechanosome containing β₃ integrins. PKGII-null mice showed defective Src and ERK (extracellular signal–regulated kinase) signaling in osteoblasts and decreased ERK-dependent gene expression in bone. Our findings reveal a convergence of NO-cGMP-PKG and integrin signaling and establish a previously unknown mechanism of Src activation. These results support the use of PKG-activating drugs to mimic the anabolic effects of mechanical stimulation of bone in the treatment of osteoporosis.