Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery

Estrogen is imperative to mammalian reproductivity,metabolism,and aging.However,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain malignancies.In contrast,ERβis more broadly expressed in metabolic tissues and the skin.Thus,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERαactivation.Here,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or genistein.Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in vitro.We further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound healing.Therefore,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

D-ribose increases triglyceride via upregulation of DGAT in the liver

Dear Editor, Fatty liver disease or hepatic steatosis, recognized as the hepatic component of metabolic syndrome, can progress to cirrhosis and hepatocellular carcinoma (Youngwanichsetha, 2018).

Acetylation of PPARγin macrophages promotes visceral fat degeneration in obesity

Obesity is characterized by chronic,low-grade inflammation,which is driven by macrophage infiltration of adipose tissue.PPARγ is well established to have an anti-inflammatory function in macrophages,but the mechanism that regulates its function in these cells remains to be fully elucidated.PPARγundergoes post-translational modifications(PTMs),including acetylation,to mediate ligand responses,including on metabolic functions.Here,we report that PPARγacetylation in macrophages promotes their infiltration into adipose tissue,exacerbating metabolic dysregulation.We generated a mouse line that expresses a macrophage-specific,constitutive acetylation-mimetic form of PPARγ(K293Q^(flox/flox):LysM-cre,mK293Q)to dissect the role of PPARγacetylation in macrophages.Upon highfat diet feeding to stimulate macrophage infiltration into adipose tissue,we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice,including responses to the PPARγagonist Rosiglitazone.Macrophage-specific PPARγK293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue,but not in subcutaneous or brown adipose tissue,leading to decreased energy expenditure,insulin sensitivity,glucose tolerance,and adipose tissue function.Furthermore,mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling.Our study reveals that acetylation is a new layer of PPARγregulation in macrophage activation,and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.