Accumulation of auranofin in white adipose tissues lowers leptin levels and exerts anti-diabetic effects

SUMMARYLow-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and frequently coincides with insulin resistance and type 2 diabetes (T2D). However, pharmacological targeting of WAT inflammation lacks durable therapeutic effects. Through a computational screen, we identified the FDA-approved rheumatoid arthritis drug auranofin is a putative small molecule for obesity treatment. We discovered that allometrically scaled safe auranofin doses homed to WAT and improved insulin sensitivity in obese wild-type mice. Auranofin treatment also normalized other obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia. Surprisingly, the anti-diabetic effects of auranofin required leptin lowering and beta-adrenergic receptors in WAT. These metabolic benefits of leptin reduction were superior to any immune impacts of auranofin in WAT. Our studies reveal important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2D.

Beta-Arrestins in the Treatment of Heart Failure Related to Hypertension: A Comprehensive Review

Heart failure (HF) is a complicated clinical syndrome that is considered an increasingly frequent reason for hospitalization, characterized by a complex therapeutic regimen, reduced quality of life, and high morbidity. Long-standing hypertension ultimately paves the way for HF. Recently, there have been improvements in the treatment of hypertension and overall management not limited to only conventional medications, but several novel pathways and their pharmacological alteration are also conducive to the treatment of hypertension. Beta-arrestin (β-arrestin), a protein responsible for beta-adrenergic receptors’ (β-AR) functioning and trafficking, has recently been discovered as a potential regulator in hypertension. β-arrestin isoforms, namely β-arrestin1 and β-arrestin2, mainly regulate cardiac function. However, there have been some controversies regarding the function of the two β-arrestins in hypertension regarding HF. In the present review, we try to figure out the paradox between the roles of two isoforms of β-arrestin in the treatment of HF.

You beta block: or not?

β-blockers bind selectively to beta-adrenergic receptors and interfere with catecholamines provoking β-responses on the heart and smooth muscles of the airways and blood vessels. To block or not to block.

Environmental enrichment reverses memory impairment in B3-ARKO mice

ABSTRACTNorepinephrine plays an important role in modulating the processes of memory consolidation and evocation through its beta-adrenergic receptors (Adrβ), which are expressed in the hippocampus and amygdala. Several studies have shown that all three subtypes of Adrβ (β1, β2 and β3) play an important role in cognition. Environmental enrichment (EE), a technique initially used to decrease the stress of animals held in captive environments, has also been shown to produce cognitive benefits in both healthy and sick animals. In this study, we hypothesized that EE would reverse the memory impairment induced by the absence or Adrβ3. To test this, 21- and 86-day-old Adrβ3KO mice were exposed to an EE protocol for 8 weeks. The study showed that the EE protocol is able to correct the memory impairment when applied to Adrβ3KO animals immediately after weaning but has no effect when applied to adult animals. We also found that aging worsens the memory of Adrβ3KO mice. Our results suggest that a richer and more diverse environment helps to correct memory impairment in Adrβ3KO animals. They also reinforce the idea that noradrenergic signaling is involved in the cognitive impairment observed late in life, as aging led to a worsening in the memory of the Adrβ3KO animals that was not corrected by the environmental enrichment protocol.

Abstract 407: Beta-blockers Reverse Beta Adrenergic Receptors Desensitization Under Hypoxia

Hypoxia to heart or brain is a primary cause of heart failure or stroke. Studies have shown that hypoxia increases the beta-adrenergic receptors (βARs) phosphorylation and dysfunction (Cheong et. al., 2016). These observations provide evidence that βARs can directly be regulated by hypoxia but less is known about the underlying mechanisms. We postulated that hypoxia shifts the homeostasis between kinase and phosphatase driven mechanisms may underlie βAR dysfunction. β2AR HEK 293 cells were exposed to hypoxia (2% O 2 ) and assessed the mechanisms underlying desensitization (G-protein coupled receptor kinases, GRKs) and resensitization (Protein phosphatase 2A, PP2A). Six hours of hypoxia treatment resulted in increase of βAR phosphorylation and GRK2 expression, and interestingly, the internalization of phosphorylated β2AR is β-arrestin independent. Assessment of βAR phosphorylation in the plasma membrane and endosomal fractions surprisingly, showed marked increase in β2AR phosphorylation in the endosomal fraction. Furthermore, we also observed that receptor associated PP2A activity was inhibited in the endosomes following hypoxia with minimal changes of activity at the plasma membranes. At the same time, PI3Kγ activity markedly upregulated in the endosomes along with an increase of I2PP2A phosphorylation. Similarly subjecting normal mice to 20 hours of hypoxia resulted in significant cardiac dysfunction (% FS: Normoxia 38.83% vs. Hypoxia 32.38%, P=0.0055; % EF: Normoxia 69.71% vs. Hypoxia 60.76%,P=0.0105) and was associated with significant increase in β2AR phosphorylation associated with significant loss in βAR function as measured by G-protein coupling adenylyl cyclase activity. Given that β-blockers confer beneficial effects, we tested whether β-blocker (propranolol) would prevent βARs phosphorylation under hypoxia or normoxia. Consistently, β-blocker treatment in normoxia results in increased β2AR phosphorylation however, remarkably β-blocker treatment in hypoxia results in loss of β2AR phosphorylation, reduction in GRK2 expression and increase in βAR-associated PP2A. These studies show that agonist-independent hypoxia-driven β2AR dysfunction can be ameliorated by β-blockers and the underlying mechanisms for this unexpected findings will be discussed in the presentation. These findings have significant clinical implications as understanding these mechanisms could provide novel insights into the benefits provided by β-blockers.