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Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with higher rates of recurrence and distant metastasis, as well as decreased 5-year survival rates. Racial disparities are evident in the incidence and mortality rates of triple negative breast cancer particularly increased in young African American women. Concurrently, young African American women have multiple risk factors for TNBC including higher rates of premenopausal abdominal obesity (higher waist-hip ratio) and lower rates of breastfeeding with higher parity, implicating these factors as potentially contributors to poor outcomes. By understanding the mechanisms of how premenopausal obesity and lack of breastfeeding may be associated with increased risk of triple negative breast cancer, we can determine the best strategies for intervention and awareness to improve outcomes in TNBC. [ABSTRACT FROM AUTHOR]

Metabolic diseases, notably obesity and type 2 diabetes (T2D), have reached alarming proportions and constitute a significant global health challenge, emphasizing the urgent need for effective preventive and therapeutic strategies. In contrast, exercise training emerges as a potent intervention, exerting numerous positive effects on metabolic health through adaptations to the metabolic tissues. Here, we reviewed the major features of our current understanding with respect to the intricate interplay between metabolic diseases and key metabolic tissues, including adipose tissue, skeletal muscle, and liver, describing some of the main underlying mechanisms driving pathogenesis, as well as the role of exercise to combat and treat obesity and metabolic disease. [ABSTRACT FROM AUTHOR]

ObjectiveChylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear.Approach and resultsTriglyceride-rich lipoprotein clearance was measured in AlbCre(+)Ndst1(f/f), Ldlr(-/-), and AlbCre(+)Lrp1(f/f) mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all 3 receptors (AlbCre(+)Ndst1(f/f) Lrp1(f/f) Ldlr(-/-)) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (≈ 20-40 nm diameter), whereas LDLR and LRP1 clear larger particles (≈ 40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem to play a less significant role on a high-fat diet.ConclusionsThese data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.

Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional [Ca.sup.2+]/calmodulin-dependent kinase II (CaMKII) has emerged as a critical regulator of cardiac hypertrophy and failure, although the mechanisms remain unclear. Previous studies have established that the cytoskeletal protein [[beta].sub.IV]-spectrin coordinates local CaMKII signaling. Here, we sought to determine the role of a spectrin-CaMKII complex in maladaptive remodeling in HF. Chronic pressure overload (6 weeks of transaortic constriction [TAC]) induced a decrease in cardiac function in WT mice but not in animals expressing truncated [[beta].sub.IV]-spectrin lacking spectrin-CaMKII interaction ([qv.sub.3J] mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in [qv.sub.3J] TAC hearts. In vitro experiments demonstrated that [[beta].sub.IV]-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific [[beta].sub.IV]-spectrin-KO ([[beta].sub.IV]-cKO) mice showed STAT3 dysregulation, fibrosis, and decreased cardiac function at baseline, similar to what was observed with TAC in WT mice. STAT3 inhibition restored normal cardiac structure and function in [[beta].sub.IV]-cKO and WT TAC hearts. Our studies identify a spectrin-based complex essential for regulation of the cardiac response to chronic pressure overload. We anticipate that strategies targeting the new spectrin-based 'statosome' will be effective at suppressing maladaptive remodeling in response to chronic stress., IntroductionHeart failure (HF) represents a major burden on the US health care system, with 870,000 new cases annually and a total cost of $30.7 billion. By 2030, the incidence of [...]

BackgroundLipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism.Methods and findingsWe examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia.ConclusionsThis is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.

Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle.

Autologous adipose tissue is commonly used for tissue engraftment for the purposes of soft tissue reconstruction due to its relative abundance in the human body and ease of acquisition using liposuction methods. This has led to the adoption of autologous adipose engraftment procedures that allow for the injection of adipose tissues to be used as a "filler" for correcting cosmetic defects and deformities in soft tissues. However, the clinical use of such methods has several limitations, including high resorption rates and poor cell survivability, which lead to low graft volume retention and inconsistent outcomes. Here, we describe a novel application of milled electrospun poly(lactic‐co‐glycolic acid) (PLGA) fibers, which can be co‐injected with adipose tissue to improve engraftment outcomes. These PLGA fibers had no significant negative impact on the viability of adipocytes in vitro and did not elicit long‐term proinflammatory responses in vivo. Furthermore, co‐delivery of human adipose tissue with pulverized electrospun PLGA fibers led to significant improvements in reperfusion, vascularity, and retention of graft volume compared to injections of adipose tissue alone. Taken together, the use of milled electrospun fibers to enhance autologous adipose engraftment techniques represents a novel approach for improving upon the shortcomings of such methods. [ABSTRACT FROM AUTHOR]

Diabetes strongly impacts protein metabolism, particularly in skeletal muscle. Insulin and IGF-1 enhance muscle protein synthesis through their receptors, but the relative roles of each in muscle proteostasis have not been fully elucidated. Using mice with muscle-specific deletion of the insulin receptor ([M-IR.sup.-/-] mice), the IGF-1 receptor (M-[IGF1R.sup.-/-] mice), or both (MIGIRKO mice), we assessed the relative contributions of IR and IGF1R signaling to muscle proteostasis. In differentiated muscle, IR expression predominated over IGF1R expression, and correspondingly, [M-IR.sup.-/-] mice displayed a moderate reduction in muscle mass whereas [M-IGF1R.sup.-/-] mice did not. However, these receptors serve complementary roles, such that double-knockout MIGIRKO mice displayed a marked reduction in muscle mass that was linked to increases in proteasomal and autophagy-lysosomal degradation, accompanied by a high- protein-turnover state. Combined muscle-specific deletion of FoxO1, FoxO3, and FoxO4 in MIGIRKO mice reversed increased autophagy and completely rescued muscle mass without changing proteasomal activity. These data indicate that signaling via IR is more important than IGF1R in controlling proteostasis in differentiated muscle. Nonetheless, the overlap of IR and IGF1R signaling is critical to the regulation of muscle protein turnover, and this regulation depends on suppression of FoxO-regulated, autophagy-mediated protein degradation., Introduction Muscle wasting and the associated decrease in muscle strength cause significant morbidity and predict risk of mortality in elderly individuals (1). A diverse range of insults including aging, immobility, [...]