Impaired estrogen receptor α(ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERαexpression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERαknockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A–regulator of calcineurin 1–calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERαdeficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERαin the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women.
ERα is expressed in macrophages and other immune cells known to exert dramatic effects on glucose homeostasis. We investigated the impact of ERα expression on macrophage function to determine whether hematopoietic or myeloid-specific ERα deletion manifests obesity-induced insulin resistance in mice. Indeed, altered plasma adipokine and cytokine levels, glucose intolerance, insulin resistance, and increased adipose tissue mass were observed in animals harboring a hematopoietic or myeloid-specific deletion of ERα. A similar obese phenotype and increased atherosclerotic lesion area was displayed in LDL receptor-KO mice transplanted with ERα −/− bone marrow. In isolated macrophages, ERα was necessary for repression of inflammation, maintenance of oxidative metabolism, IL-4–mediated induction of alternative activation, full phagocytic capacity in response to LPS, and oxidized LDL-induced expression of ApoE and Abca1. Furthermore, we identified ERα as a direct regulator of macrophage transglutaminase 2 expression, a multifunctional atheroprotective enzyme. Our findings suggest that diminished ERα expression in hematopoietic/myeloid cells promotes aspects of the metabolic syndrome and accelerates atherosclerosis in female mice.
Increased heat shock protein (HSP) 72 expression in skeletal muscle prevents obesity and glucose intolerance in mice, although the underlying mechanisms of this observation are largely unresolved. Herein we show that HSP72 is a critical regulator of stress-induced mitochondrial triage signaling since Parkin, an E3 ubiquitin ligase known to regulate mitophagy, was unable to ubiquitinate and control its own protein expression or that of its central target mitofusin (Mfn) in the absence of HSP72. In wild-type cells, we show that HSP72 rapidly translocates to depolarized mitochondria prior to Parkin recruitment and immunoprecipitates with both Parkin and Mfn2 only after specific mitochondrial insult. In HSP72 knockout mice, impaired Parkin action was associated with retention of enlarged, dysmorphic mitochondria and paralleled by reduced muscle respiratory capacity, lipid accumulation, and muscle insulin resistance. Reduced oxygen consumption and impaired insulin action were recapitulated in Parkin-null myotubes, confirming a role for the HSP72-Parkin axis in the regulation of muscle insulin sensitivity. These data suggest that strategies to maintain HSP72 may provide therapeutic benefit to enhance mitochondrial quality and insulin action to ameliorate complications associated with metabolic diseases, including type 2 diabetes.
Head and neck cancer is the ninth most common cancer in the USA, accounting for 3.3 % of all cancers. The incidence of head and neck cancer has plateaued recently; however, morbidity and mortality continue to remain high. Moreover, racial disparity between African-American and White patients has been studied in the head and neck community, and a vast difference still remains in mortality rate and late stage at presentation. A review of the English literature was performed using PubMed/MEDLINE for demographics, epidemiology, and studies that focused on the disparity in head and neck cancer between African-American and White patients. Age-adjusted incidence of head and neck cancer is increased in African-Americans, while the 5-year survival is decreased compared to Whites. African-American patients present with more advanced disease. When receiving similar multidisciplinary care, the overall survival was not significantly different, but racial disparity often persists in treatment regimens. Socioeconomic determinants such as insurance status play a critical role in racial disparity, along with low levels of public awareness, a lack of knowledge of specific risk factors, and a sense of mistrust that is seen in the African-American population. Disparity in the head and neck cancer community is worrisome, and although efforts have been taken to decrease the disparity, a significant difference exists. Fortunately, the disparity is reversible and can be eliminated. To do so, it is critical to extend to underserved community programs that provide appropriate screening and diagnosis, with subsequent follow-up and treatment following the standards of care.
Background: Mechanisms underlying obesity-associated breast cancer incidence are incompletely understood. Results: Adipose tissue estrogen receptor (ER)␣ expression is inversely associated with adiposity and the expression and release of Lcn2, an adipokine promoting breast cancer cell proliferation and migration. Conclusion: ER␣ is critical for restraining adiposity and Lcn2 production. Significance: Modulation of adipose tissue ER␣ action is a potential approach to prevent obesity and reduce breast cancer risk.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.