Nesfatin-1 Acts Centrally to Induce Sympathetic Activation of Brown Adipose Tissue and Non-Shivering Thermogenesis.

Nesfatin-1 has originally been established as a bioactive peptide interacting with key hypothalamic nuclei and neural circuitries in control of feeding behavior, while its effect on energy expenditure has only recently been investigated. Hence, the aim of this study was to examine whether centrally acting nesfatin-1 can induce ß3-adrenergic stimulation, which is a prerequisite for the activation of thermogenic genes and heat release from interscapular brown adipose tissue, key physiological features that underlie increased energy expenditure. This question was addressed in non-fasted mice stereotactically cannulated to receive nesfatin-1 intracerebroventricularly together with peripheral injection of the ß3-adrenoceptor antagonist SR 59230 A, to assess whole-body energy metabolism. Using a minimally invasive thermography technique, we now demonstrate that the thermogenic effect of an anorectic nesfatin-1 dose critically depends on ß3 adrenergic stimulation, as the co-administration with SR 59230 A completely abolished heat production from interscapular brown adipose tissue and rise in ocular surface temperature, thus preventing body weight loss. Moreover, through indirect calorimetry it could be shown that the anorectic concentration of nesfatin-1 augments overall caloric expenditure. Plausibly, central administration of nesfatin-1 also enhanced the expression of DIO2 and CIDEA mRNA in brown adipose tissue critically involved in the regulation of thermogenesis.

AUGS Consensus Statement: Association of Anticholinergic Medication Use and Cognition in Women With Overactive Bladder.

Overactive bladder affects a significant portion of the overall population and has substantial impact on daily activities and quality-of-life. When considering treatment, behavioral therapies should be instituted first, followed by medical therapies. Anticholinergic medications and beta-3 agonists are often used as initial pharmacologic therapy, but caution should be taken in prescribing anticholinergic medications in frail or cognitively impaired patients. Recently, concerns have developed regarding anticholinergic medications and the associated risk of cognitive impairment, dementia, and Alzheimer disease in the general population. Given the available evidence, which has shown significant associations between anticholinergic medication use and increased risk of cognitive impairment and dementia, providers should counsel on the associated risks, prescribe the lowest effective dose, and consider alternative medications in patients at risk.

Targeting ß3-Adrenergic Receptors in the Heart: Selective Agonism and ß-Blockade.

Cardiac diseases, such as heart failure, remain leading causes of morbidity and mortality worldwide, with myocardial infarction as the most common etiology. HF is characterized by ß-adrenergic receptor (ßAR) dysregulation that is primarily due to the upregulation of G protein-coupled receptor kinases that leads to overdesensitization of ß1 and ß2ARs, and this clinically manifests as a loss of inotropic reserve. Interestingly, the "minor" ßAR isoform, the ß3AR, found in the heart, lacks G protein-coupled receptor kinases recognition sites, and is not subject to desensitization, and as a consequence of this, in human failing myocardium, the levels of this receptor remain unchanged or are even increased. In different preclinical studies, it has been shown that ß3ARs can activate different signaling pathways that can protect the heart. The clinical relevance of this is also supported by the effects of ß-blockers which are well known for their proangiogenic and cardioprotective effects, and data are emerging showing that these are mediated, at least in part, by enhancement of ß3AR activity. In this regard, targeting of ß3ARs could represent a novel potential strategy to improve cardiac metabolism, function, and remodeling.

Functional involvement of ß3-adrenergic receptors in melanoma growth and vascularization.

UNLABELLED: ß-adrenergic signaling is thought to facilitate cancer progression and blockade of ß-adrenergic receptors (ß-ARs) may slow down tumor growth. A possible role of ß3-ARs in tumor growth has not been investigated so far and the lack of highly specific antagonists makes difficult the evaluation of this role. In the present study, ß3-AR expression in mouse B16F10 melanoma cells was demonstrated and the effects of two widely used ß3-AR blockers, SR59230A and L-748,337, were evaluated in comparison with propranolol, a ß1-/ß2-AR blocker with poor affinity for ß3-ARs, and with siRNAs targeting specific ß-ARs. Both SR59230A and L-748,337 reduced cell proliferation and induced apoptosis, likely through the involvement of the inducible isoform of nitric oxide synthase. In addition, hypoxia upregulated ß3-ARs and vascular endothelial growth factor (VEGF) in B16F10 cells, whereas SR59230A or L-748,337 prevented the hypoxia-induced VEGF upregulation. Melanoma was induced in mice by inoculation of B16F10 cells. Intra-tumor injections of SR59230A or L-748,337 significantly reduced melanoma growth by reducing cell proliferation and stimulating apoptosis. SR59230A or L-748,337 treatment also resulted in significant decrease of the tumor vasculature. The decrease in tumor vasculature was due to apoptosis of endothelial cells and not to downregulation of angiogenic factors. These results demonstrate that SR59230A and L-748,337 significantly inhibit melanoma growth by reducing tumor cell proliferation and activating tumor cell death. In addition, both drugs reduce tumor vascularization by inducing apoptosis of endothelial cells. Together, these findings indicate ß3-ARs as promising, novel targets for anti-cancer therapy. KEY MESSAGE: ß3-ARs are expressed in B16F10 melanoma cells ß3-ARs are involved in B16F10 cell proliferation and apoptosis Reduced ß3-AR function decreases the growth of melanoma induced by B16F10 cell inoculation Drugs targeting ß3-ARs reduce tumor vasculature ß3-ARs can be regarded as promising, novel targets for anti-cancer therapy.

Involvement of ß3-adrenergic receptors in the control of food intake in rats.

This study examined the food intake changes evoked by intracerebroventricular (icv) injection of a selective agonist (BRL37344, 2 and 20 nmol) or antagonist (SR59230A, 10 and 50 nmol) of ß3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment). The animals were also pretreated with saline icv (SAL) or SR59230A (50 nmol) followed by BRL37344 (20 nmol) or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA) behavior. The highest dose of BRL37344 (N = 7) decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats). While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol), this treatment reduced the RA frequency (number/30 min) (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats), an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g) abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g), BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by ß3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.