Biology subjects

Alexander, C. M.

Publications and source records attributed to Alexander, C. M..

4 recordsLinked to original sources

bioRxiv2025

Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia

Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.

cancer biology↗

bioRxiv2024

Dietary lipid is largely deposited in skin and rapidly affects insulating properties

Skin has been shown to be a regulatory hub for energy expenditure and metabolism: mutations of skin lipid metabolism enzymes can change the rate of thermogenesis and susceptibility to diet-induced obesity. However, little is known about the physiological basis for this function. Here we show that the thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We found that skin was the largest target in a mouse body for dietary fat delivery, and that dietary triglyceride was assimilated both by epidermis and by dermal white adipose tissue. Skin from mice calorie-restricted for 3 weeks did not take up circulating lipids and showed a highly depleted stratum corneum. Dietary triglyceride acyl groups persist in skin for weeks after feeding. Using multi-modal lipid profiling, we have implicated both keratinocytes and sebocytes in the altered lipids which correlate with thermal function. In response to high fat feeding, wax diesters and ceramides accumulate, and triglycerides become more saturated. In contrast, in response to the dramatic loss of adipose tissue that accompanies restriction of the branched chain amino acid isoleucine, skin becomes more heat-permeable, resisting changes induced by Western diet feeding, with a signature of depleted signaling lipids. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality.

physiology↗

bioRxiv2022

Regulation of metabolic health by dietary histidine in mice

Low protein (LP) diets are associated with a decreased risk of diabetes in humans, and a low protein diet promotes leanness and glycemic control in both rodents and humans. While the effects of a LP diet on glycemic control are mediated by reduced dietary levels of the branched- chain amino acids (BCAAs), we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to a LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces weight gain of young, lean male mice, reducing both adipose and lean mass gain, without altering glucose metabolism. Specifically reducing dietary histidine rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity; this normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. We find that the effects of histidine restriction surprisingly does not require the energy balance hormone Fgf21. Histidine restriction started in mid-life promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary levels of histidine may be a highly translatable option for the treatment of obesity. Key PointsO_LIProtein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. C_LIO_LIRestriction of specific individual essential amino acids can recapitulate the benefits of PR. C_LIO_LIReduced histidine promotes leanness and increased energy expenditure in mice. C_LIO_LIReduced histidine does not extend the lifespan of mice when begun in mid-life. C_LIO_LIDietary levels of histidine are positively associated with BMI in humans. C_LI

physiology↗

bioRxiv2021

Enhanced Immunoprecipitation Techniques for the Identification of RNA Binding Protein Partners: CRD-BP interactions in mammary epithelial cells

RNA binding proteins (RBPs) regulate expression of large cohorts of RNA species to affect programmatic changes in cellular phenotypes. In order to describe the function of RBPs within a cell, it is key to identify their mRNA binding partners. This is often done by cross-linking nucleic acids to RBPs, followed by chemical release of the nucleic acid fragments for analysis. However, this methodology is lengthy, involves complex processing leading to extraordinary losses, requires large amounts of starting materials, and is prone to artifacts due to the labile nature of mRNA. To evaluate potential alternative technologies, we tested "exclusion-based" purification of immunoprecipitates (oil-based IFAST or air-based SLIDE), and report here that these methods can efficiently, rapidly and specifically isolate RBP-RNA complexes with minimal handling. The analysis starts with >100x less material than for techniques that include cross-linking. Depending on the specific antibody used, 50-100% of starting protein is retrieved, allowing the assay of endogenous levels of RBP instead of tagged and over-expressed ectopic proteins. Isolated protein and nucleic acid components are purified and analyzed using standard techniques to provide a comprehensive portrait of RBP complexes. Using exclusion-based techniques, we show that the mRNA binding partners for CRD-BP/IMP1/IGF2BP1/ZBP1 in cultured mammary epithelial cells are enriched in mRNAs important for de-toxifying superoxides (glutathione metabolic enzymes) and other mRNAs encoding mitochondrial proteins.

molecular biology↗