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.

Nanomedicine for obesity treatment

Obesity, as a chronic condition, has been a serious public health issue over the last decades both in the affluent Western world and developing countries. As reported, the risk of several serious diseases increases with weight gain, including type 2 diabetes,coronary heart disease, cancer, and respiratory diseases. In addition to lifestyle modifications, pharmacotherapy has become an important strategy to control weight gain. However, most of the anti-obesity drugs often show poor outcome for weight-loss and cause severe adverse effects. This review surveys recent advances in nanomedicine as an emerging strategy for obesity treatment with an emphasis on the enhanced therapeutic efficiency and minimized side effects. The insights for future development are also discussed.

The dark side of browning

The induction of brown-like adipocyte development in white adipose tissue （WAT） confers numerous metabolic benefits by decreasing adiposity and increasing energy expenditure. Therefore, WAT browning has gained considerable attention for its potential to reverse obesity and its associated co-morbidities. However, this perspective has been tainted by recent studies identifying the detrimental effects of inducing WAT browning. This review aims to highlight the adverse outcomes of both overactive and underactive browning activity, the harmful side effects of browning agents, as well as the molecular brake-switch system that has been proposed to regulate this process. Developing novel strategies that both sustain the metabolic improvements of WAT browning and attenuate the related adverse side effects is therefore essential for unlocking the therapeutic potential of browning agents in the treatment of meta- bolic diseases.

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.

Developmental thyroid hormone action on pro-opiomelanocortin-expressing cells programs hypothalamic BMPR1A depletion and brown fat activation

Thyroid hormone excess secondary to global type 3 deiodinase(DIO3)deficiency leads to increased locomotor activity and reduced adiposity,but also to concurrent alterations in parameters of the leptin-melanocortin system that would predict obesity.To distinguish the underlying contributions to the energy balance phenotype of Dlo3 deficiency,we generated mice with thyroid hormone excess targeted to pro-opiomelanocortin(POMC)-expressing cells via cell-specific DIO3 inactivation.These mice exhibit a male-specific phenotype of reduced hypothalamic Pomc expression,hyperphagia,and increased activity in brown adipose tissue,with adiposity and serum levels of leptin and thyroid hormones remained normal.These male mice also manifest a marked and widespread hypothalamic reduction in the expression of bone morphogenetic receptor 1a(BMPR1A),which has been shown to cause similar phenotypes when inactivated in PoMC-expressing cells.Our results indicate that developmental overexposure to thyroid hormone in PoMC-expressing cells programs energy balance mechanisms in a sexually dimorphic manner by suppressing adult hypothalamic BMPR1A expression.

The polarizable and reprogrammable identity of Kupffer cells in Nonalcoholic Steatohepatitis

Kupffer cells(KCs)are the resident macrophages of the liver with similar origins to myeloid-derived macrophages.Once differentiated,KCs exhibit distinct cellular machinery capable of longevity and self-renewal,making them a crucial player in promoting effective intrahepatic communication.However,this gets compromised in disease states like Nonalcoholic Steatohepatitis(NASH),where the loss of embryo-derived KCs(EmKCs)is observed.Despite this,other KC-like and KC-derived populations start to form and contribute to a variety of roles in NASH pathogenesis,often adopting a NASH-associated molecular signature.Here we offer a brief overview of recent reports describing KC polarization and reprogramming in the liver.We describe the complexities of KC cellular identity,their proposed ability to reprogram to fibroblast-like and endothelial-like cells,and the potential implications in NASH.