Better together: Coalitions committed to advancing health equity.

The Future of Nursing 2020-2030 report identifies coalitions as a driving force for advancing health equity. Five coalitions provided insight into their accomplishments, lessons learned, and role in advancing health equity. The exemplar coalitions included Latinx Advocacy Team and Interdisciplinary Network for COVID-19, Black Coalition Against COVID, Camden Coalition, National Coalition of Ethnic Minority Nurse Associations, and The Future of Nursing: Campaign for Action. While all exemplar coalitions, credited relationship building and partnerships to their success, they used unique strategies for striving to meet their populations' needs, whether the needs arose from COVID-19, racial and/or ethnic disparities, socioeconomic disparities, or other barriers to health. Research and policy implications for coalitions are discussed. Nurses play a critical role in every highlighted coalition and in the national effort to make health and health care more equitable.

Leptin-dependent phosphorylation of PTEN mediates actin restructuring and activation of ATP-sensitive K+ channels.

Leptin activates multiple signaling pathways in cells, including the phosphatidylinositol 3-kinase pathway, indicating a degree of cross-talk with insulin signaling. The exact mechanisms by which leptin alters this signaling pathway and how it relates to functional outputs are unclear at present. A previous study has established that leptin inhibits the activity of the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), an important tumor suppressor and modifier of phosphoinositide signaling. In this study we demonstrate that leptin phosphorylates multiple sites on the C-terminal tail of PTEN in hypothalamic and pancreatic beta-cells, an action not replicated by insulin. Inhibitors of the protein kinases CK2 and glycogen synthase kinase 3 (GSK3) block leptin-mediated PTEN phosphorylation. PTEN phosphorylation mutants reveal the critical role these sites play in transmission of the leptin signal to F-actin depolymerization. CK2 and GSK3 inhibitors also prevent leptin-mediated F-actin depolymerization and consequent ATP-sensitive K(+) channel opening. GSK3 kinase activity is inhibited by insulin but not leptin in hypothalamic cells. Both hormones increase N-terminal GSK3 serine phosphorylation, but in hypothalamic cells this action of leptin is transient. Leptin, not insulin, increases GSK3 tyrosine phosphorylation in both cell types. These results demonstrate a significant role for PTEN in leptin signal transmission and identify GSK3 as a potential important signaling node contributing to divergent outputs for these hormones.

A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic beta-cells.

In obesity and diabetes, the ability of hypothalamic neurons to sense and transduce changes in leptin and insulin levels is compromised. The effects of both hormones require intracellular signalling via the PI3-kinase pathway, which is inhibited by the phosphatase PTEN. We show that leptin-stimulated F-actin depolymerization in mouse hypothalamic cells is inhibited by PTEN, a process involving independent effects of both its lipid and protein phosphatase activities. Potentially mediating this F-actin depolymerization, leptin, but not insulin, stimulated the phosphorylation of PTEN in a CK2 dependent manner, and inhibited its phosphatase activity. Similarly, hyperpolarization of mouse pancreatic beta-cells by leptin also requires coincident PtdIns(3,4,5)P3 generation and actin depolymerization, and could be inhibited by mechanisms requiring both the lipid and protein phosphatase activities of PTEN. These results demonstrate a critical role for PTEN in leptin signalling and indicate a mechanism by which leptin and insulin can produce PI3K dependent differential cellular outputs.

Circulating melanin-concentrating hormone, agouti-related protein, and alpha-melanocyte-stimulating hormone levels in relation to body composition: alterations in response to food deprivation and recombinant human leptin administration.

We evaluated whether circulating levels of melanin-concentrating hormone (MCH), agouti-related protein (AGRP), and alpha-MSH could serve as useful markers of energy homeostasis in humans. We first assessed correlations of serum MCH, AGRP, and alpha-MSH with anthropometric, dietary, and hormonal variables in a cross-sectional study of 108 healthy humans. We then performed interventional studies to evaluate the effects of fasting and/or leptin administration. In eight healthy, normal weight men, we measured serum MCH, AGRP, and alpha-MSH levels at baseline, after 2 d of fasting alone (a low leptin state), and after 2 d of fasting with replacement dose recombinant methionyl human leptin (r-metHuLeptin) administration to normalize circulating leptin levels. In a separate group of five lean and five obese men, we measured MCH levels in response to increasing circulating leptin levels to the pharmacological range by administration of one r-metHuLeptin dose in the fed state. In the cross-sectional study, serum MCH levels were independently and positively associated with body mass index and fat mass and were higher in women than in men. Furthermore, in our interventional studies, fasting for 2 d significantly decreased leptin levels and increased serum MCH levels. Administration of replacement dose r-metHuLeptin during fasting prevented the fasting-induced increase in MCH levels, but administration of a pharmacological r-metHuLeptin dose in the fed state did not further alter MCH levels. Serum AGRP levels tended to change in directions similar to MCH, but this change was less pronounced and needs to be investigated in larger studies. In contrast, serum alpha-MSH levels did not correlate with body composition parameters, were not associated with caloric or macronutrient intake, and were not significantly affected by fasting or r-metHuLeptin administration. These findings suggest that serum MCH and possibly AGRP levels could serve as useful peripheral markers of changes in energy homeostasis and thus merit additional investigation.

Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies.

Adiponectin is an adipocyte-secreted protein that circulates in high concentrations in the serum and acts to increase insulin sensitivity. Previous studies have shown that serum adiponectin is inversely associated with fat mass and insulin resistance in humans and that acute fasting decreases adipose tissue adiponectin mRNA expression in rodents. Whether acute energy deprivation, body fat distribution, or serum hormone levels are associated with circulating adiponectin in humans remains largely unknown. To identify predictors of serum adiponectin levels, we evaluated the association of adiponectin with several anthropometric, metabolic, and hormonal variables in a cross-sectional study of 121 women without a known history of diabetes. We also performed interventional studies to assess whether fasting for 48 h and/or leptin administration regulates serum adiponectin in healthy men and women. Our cross-sectional study shows that, in addition to overall obesity, central fat distribution is an independent negative predictor of serum adiponectin and suggests that adiponectin may represent a link between central obesity and insulin resistance. In addition, estradiol is negatively and independently associated with adiponectin, whereas there is no association between serum adiponectin and leptin, cortisol, or free testosterone levels. Our interventional studies demonstrate that neither fasting for 48 h, resulting in a low leptin state, nor leptin administration at physiological or pharmacological doses alters serum adiponectin levels. Further studies are needed to fully elucidate the physiology of adiponectin in humans and its role in the pathogenesis of insulin-resistant states.