. 11␤-Hydroxysteroid dehydrogenase type 1 shRNA ameliorates glucocorticoid-induced insulin resistance and lipolysis in mouse abdominal adipose tissue.

The prereceptor activation of glucocorticoid production in adipose tissue by NADPH-dependent 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1) has emerged as a potential mechanism in the pathogenesis of visceral obesity and metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) is an endoplasmic reticulum lumen-resident enzyme that generates cofactor NADPH and thus mediates 11␤-HSD1 activity. To determine the role of adipose H6PDH in the prereceptor modulation of 11␤-HSD1 and metabolic phenotypes, we generated a transgenic (Tg) mouse model overexpressing H6PDH under the control of the enhancerpromoter region of the adipocyte fatty acid-binding protein (aP2) gene (aP2/H6PDH Tg mice). Transgenic aP2/H6PDH mice exhibited relatively high expression of H6PDH and elevated corticosterone production with induction of 11␤-HSD1 activity in adipose tissue. This increase in corticosterone production in aP2-H6PDH Tg mice resulted in mild abdominal fat accumulation with induction of C/EBP mRNA expression and slight weight gain. Transgenic aP2/H6PDH mice also exhibited fasting hyperglycemia and glucose intolerance with insulin resistance. In addition, the aP2/H6PDH Tg mice have elevated circulating free fatty acid levels with a concomitant increased adipose lipolytic action associated with elevated HSL mRNA and Ser 660 HSL phosphorylation within abdominal fat. These results suggest that increased H6PDH expression specifically in adipose tissue is sufficient to cause intra-adipose glucocorticoid production and adverse metabolic phenotypes. These findings suggest that the aP2/H6PDH Tg mice may provide a favorable model for studying the potential impact of H6PDH in the pathogenesis of human metabolic syndrome.11␤-hydroxysteroid dehydrogenase type 1; transgenic mouse VISCERAL FAT DEPOSITION IS FREQUENTLY ASSOCIATED with metabolic syndrome, including visceral obesity, insulin resistance, hypertension, and dyslipidemia (13,22,39). However, the underlying mechanisms of these metabolic perturbations are poorly understood. Patients with glucocorticoid (GC) excess (Cushing's syndrome) promote visceral fat deposition and develop metabolic syndrome (1, 21). In adipose tissue, GCs promote lipolysis by stimulating two key enzymes, hormonesensitive lipase (HSL) and adipose triglyceride lipase (ATGL), to increase hydrolysis of triacylglycerol and release free fatty acids (FFA) in the circulation that is linked to hyperlipidemia and global insulin resistance (8, 24, 46). However, tissuespecific GC availability is regulated by an intracellular endoplasmic reticulum (ER) lumen-resident enzyme, 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1), that converts inert cortisone (11-dehydrocorticosterone in rodents) to the active glucocorticoid receptor (GR)-ligand cortisol (corticosterone in rodents) and thereby amplifies intracellular GC reproduction, particularly in adipose tissues (7,41,23,33). Increased adipose GC activation by 11␤-HSD1 leads to visceral obesity and features of the metabolic syndrome (29). Prereceptor amplification of GC ...

Importance: Climate change is affecting the earth, resulting in more extreme temperatures and weather, rising sea levels, more frequent natural disasters, and displacement of populations of plants and animals, including people and insects. These changes affect food and housing security, vector-borne illnesses, and access to clean air and water, all of which influence human health.Evidence and Results: There are a number of adverse health outcomes linked to heat, air pollution from wildfires, stress from natural disasters, and other elements of climate change. Pregnant people are especially vulnerable to the health harms resulting from climate change, namely, preterm birth, small for gestational age, hypertensive disorders of pregnancy, and other adverse reproductive health and birth outcomes. Strategies to minimize these harms include mitigation and adaptation.Conclusions and Relevance: Physicians are in a unique position to protect the health of pregnant persons and children by advocating for policy changes that address climate change and providing clinical recommendations for patients to protect themselves from the health impacts of climate hazards.Target Audience: Obstetricians and gynecologists, family physicians.Learning objectives: After participating in this activity, physicians should be better able to describe the adverse health effects and pregnancy outcomes associated with elements of climate change; and identify strategies for patients to minimize the health harms from climate change, including mitigation, adaptations, and building resilience. INTRODUCTION: WHY IS CLIMATE CHANGEA PROBLEM FOR HEALTH? Climate change is affecting the earth. We are now seeing more extreme weather and temperatures, rising sea levels, more frequent natural disasters (including wildfires, hurricanes, droughts, and flooding), and displacement of people, animals, insects, and plants around the world. [1][2][3][4] We are seeing a record number of climate-related disasters, with more than 22,000 disasters in the past 50 years, accounting for 45% of disaster-related deaths and 74% of economic losses. 5 Of the natural disasters, droughts, storms, floods, and extreme weather have led to the highest human losses. Climate change also affects food and housing security, vector-borne illness, and access to clean air and water, all of which influence human health. 6 High heat alone is linked to several adverse health outcomes, including stroke, exhaustion, faints, cramps, and, in severe heat, multiorgan dysfunction. 7 M.G.Z. is supported by funding from NIEHS P30-ES030284. This review article was supported in part by the American Academy of Pediatrics and funded in part by a cooperative agreement with the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (CDC/ATSDR). The US Environmental Protection Agency (EPA) supports the PEHSUs by providing partial funding to CDC/ATSDR through an interagency agreement. The findings and conclusions presented have not been formally disseminated by CDC/ ATSDR or ...