Objective We examined relationships between neighborhood poverty and allostatic load in a low to moderate income multiracial urban community. We tested the hypothesis that neighborhood poverty is associated with allostatic load, controlling for household poverty. We also examined the hypotheses that this association was mediated by a) psychosocial stress and b) health related behaviors. Methods Multilevel analyses were conducted using cross sectional data from a probability sample survey in Detroit, Michigan (n=919) and 2000 Census. The outcome measure was allostatic load. Independent variables included neighborhood and household poverty, psychosocial stress, and health related behaviors. Covariates included neighborhood and individual demographic characteristics. Results Neighborhood poverty was positively associated with allostatic load (p<.05), independent of household poverty and controlling for potential confounders. Relationships between neighborhood poverty were mediated by self-reported neighborhood environment stress, but not by health-related behaviors. Conclusions Findings are consistent with the hypothesis that neighborhood poverty is associated with wear and tear on physiological systems, and that this relationship is mediated through psychosocial stress. These relationships are evident after accounting for household poverty levels. Efforts to promote health equity should focus on neighborhood poverty and associated stressful environmental conditions, as well as household poverty.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression.

ObjectiveAdiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling.MethodsHere, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism.ResultsOverexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance.ConclusionThese observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids.

Repair of soft-tissue defects resulting from lumpectomy or mastectomy has become an important rehabilitation process for breast cancer patients. This study aimed to provide an adipose tissue engineering platform for soft-tissue defect repair by combining decellularized human adipose tissue extracellular matrix (hDAM) and human adipose-derived stem cells (hASCs). To derive hDAM, incised human adipose tissues underwent a decellularization process. Effective cell removal and lipid removal were proved by immunohistochemical analysis and DNA quantification. Scanning electron microscope examination showed three-dimensional nanofibrous architecture in hDAM. hDAM composition included collagen, sulfated glycosaminoglycan, and vascular endothelial growth factor but lacked major histocompatibility complex antigen I. hASC viability and proliferation on hDAM were proven in vitro. hDAM implanted subcutaneously in Fischer rats did not cause an immunogenic response, and it underwent remodeling as indicated by host cell infiltration, neovascularization, and adipose tissue formation. Fresh fat grafts (Coleman technique) and engineered fat grafts (hDAM combined with hASCs) were implanted subcutaneously in nude rats. The implanted engineered fat grafts maintained volume at week 8, and the hASCs contributed to adipose tissue formation. In summary, the combination of hDAM and hASCs provides not only a clinically translatable platform for adipose tissue engineering but also a vehicle for elucidating fat grafting mechanisms.

“Beige” adipocytes reside in white adipose tissue (WAT) and dissipate energy as heat. Several studies have shown that cold temperature can activate proopiomelanocortin-expressing (POMC) neurons and increase sympathetic neuronal tone to regulate WAT beiging. However, WAT is traditionally known to be sparsely innervated. Details regarding the neuronal innervation and more importantly, the propagation of the signal within the population of “beige” adipocytes are sparse. Here, we demonstrate that beige adipocytes display an increased cell-to-cell coupling via connexin 43 (Cx43) gap junction channels. Blocking of Cx43 channels by 18α-glycyrrhetinic acid decreases POMC activation-induced adipose tissue beiging. Adipocyte-specific deletion of Cx43 reduces WAT beiging to a level similar to that observed in denervated fat pads. In contrast, overexpression of Cx43 is sufficient to promote beiging even with mild cold stimuli. These data reveal the importance of cell-to-cell communication in adipose tissue for the propagation of limited neuronal inputs, resulting in effective beiging.