Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Protein restriction slows the development and progression of Alzheimer's disease in mice.

Over the last decade, it has become evident that dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and we and others have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice. We found that PR induces sex-specific alterations in circulating metabolites and in the brain lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Ormdl3 regulation of specific ceramides is dispensable for mouse ß-cell function and glucose homeostasis under obesogenic conditions.

Chronic elevation of sphingolipids contributes to ß-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic ß-cell pathophysiology remains unclear. Here, we generated a mouse model lacking Ormdl3 within pancreatic ß-cells (Ormdl3 ß-/-). We show that loss of ß-cell Ormdl3 does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, while Ormdl3 ß-/- mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss of Ormdl3 alone is not sufficient to impinge upon ß-cell function or whole-body glucose and insulin homeostasis, however, ß-cell-specific loss of Ormdl3 does significantly alter levels of specific sphingolipid species in islets upon high fat feeding.

Ormdl3 regulation of specific ceramides is dispensable for ß-cell function and glucose homeostasis under obesogenic conditions.

Chronic elevation of sphingolipids contributes to ß-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic ß-cell pathophysiology remains unclear. Here, we generated a mouse model lacking Ormdl3 within pancreatic ß-cells ( Ormdl3 ß-/- ). We show that loss of ß-cell Ormdl3 does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, while Ormdl3 ß-/- mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss of Ormdl3 alone is not sufficient to impinge upon ß-cell function or whole-body glucose and insulin homeostasis, but loss of Ormdl3 does alter specific sphingolipid levels.

Hepatic Oleate Regulates Insulin-like Growth Factor-Binding Protein 1 Partially through the mTORC1-FGF21 Axis during High-Carbohydrate Feeding.

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the rate-liming step of monounsaturated fatty acid biosynthesis and is a key regulator of systemic glucose metabolism. Mice harboring either a global (GKO) or liver-specific deletion (LKO) of Scd1 display enhanced insulin signaling and whole-body glucose uptake. Additionally, GKO and LKO mice are protected from high-carbohydrate diet-induced obesity. Given that high-carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how Scd1 deficiency confers metabolically beneficial phenotypes. Here we show that insulin-like growth factor-binding protein 1 (IGFBP1), a hepatokine that has been reported to enhance insulin signaling, is significantly elevated in the liver and plasma of GKO and LKO mice fed a low-fat high-carbohydrate diet. We also observed that the expression of hepatic Igfbp1 is regulated by oleic acid (18:1n9), a product of SCD1, through the mTORC1-FGF21 axis both in vivo and in vitro.

Lipid signatures of chronic pain in female adolescents with and without obesity.

BACKGROUND: Chronic pain in adolescence is associated with diminished outcomes, lower socioeconomic status in later life, and decreased family well-being. Approximately one third of adolescents with chronic pain have obesity compared to the general population. In obesity, lipid signals regulate insulin sensitivity, satiety, and pain sensation. We determined whether there is a distinct lipid signature associated with chronic pain and its co-occurrence with obesity in adolescents. METHODS: We performed global lipidomics in serum samples from female adolescents (N = 67, 13-17 years old) with no pain/healthy weight (Controls), chronic pain/healthy weight (Pain Non-obese), no pain/obesity (Obese), or chronic pain/obesity (Pain Obese). RESULTS: The Pain Non-obese group had lipid profiles similar to the Obese and Pain Obese groups. The major difference in these lipids included decreased lysophosphatidylinositol (LPI), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE) in the three clinical groups compared to the Control group. Furthermore, ceramides and sphingomyelin were higher in the groups with obesity when compared to the groups with healthy weight, while plasmalogens were elevated in the Pain Obese group only. CONCLUSIONS: Serum lipid markers are associated with chronic pain and suggest that specific lipid metabolites may be a signaling mechanism for inflammation associated with co-occurring chronic pain and obesity.

Determination of tissue contributions to the circulating lipid pool in cold exposure via systematic assessment of lipid profiles.

Plasma lipid levels are altered in chronic conditions such as type 2 diabetes and cardiovascular disease as well as during acute stresses such as fasting and cold exposure. Advances in MS-based lipidomics have uncovered a complex plasma lipidome of more than 500 lipids that serve functional roles, including as energy substrates and signaling molecules. This plasma lipid pool is maintained through regulation of tissue production, secretion, and uptake. A major challenge in understanding the lipidome complexity is establishing the tissues of origin and uptake for various plasma lipids, which is valuable for determining lipid functions. Using cold exposure as an acute stress, we performed global lipidomics on plasma and in nine tissues that may contribute to the circulating lipid pool. We found that numerous species of plasma acylcarnitines (ACars) and ceramides (Cers) were significantly altered upon cold exposure. Through computational assessment, we identified the liver and brown adipose tissue as major contributors and consumers of circulating ACars, in agreement with our previous work. We further identified the kidney and intestine as novel contributors to the circulating ACar pool and validated these findings with gene expression analysis. Regression analysis also identified that the brown adipose tissue and kidney are interactors with the plasma Cer pool. Taken together, these studies provide an adaptable computational tool to assess tissue contribution to the plasma lipid pool. Our findings have further implications in understanding the function of plasma ACars and Cers, which are elevated in metabolic diseases.

Lipid Transport in Brown Adipocyte Thermogenesis.

Non-shivering thermogenesis is an energy demanding process that primarily occurs in brown and beige adipose tissue. Beyond regulating body temperature, these thermogenic adipocytes regulate systemic glucose and lipid homeostasis. Historically, research on thermogenic adipocytes has focused on glycolytic metabolism due to the discovery of active brown adipose tissue in adult humans through glucose uptake imaging. The importance of lipids in non-shivering thermogenesis has more recently been appreciated. Uptake of circulating lipids into thermogenic adipocytes is necessary for body temperature regulation and whole-body lipid homeostasis. A wide array of circulating lipids contribute to thermogenic potential including free fatty acids, triglycerides, and acylcarnitines. This review will summarize the mechanisms and regulation of lipid uptake into brown adipose tissue including protein-mediated uptake, lipoprotein lipase activity, endocytosis, vesicle packaging, and lipid chaperones. We will also address existing gaps in knowledge for cold induced lipid uptake into thermogenic adipose tissue.

Environmental Public Health Applications Using Remotely Sensed Data.

We describe a remote sensing and GIS-based study that has three objectives: (1) characterize fine particulate matter (PM2.5), insolation and land surface temperature using NASA satellite observations, EPA ground-level monitor data and North American Land Data Assimilation System (NLDAS) data products on a national scale; (2) link these data with public health data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) national cohort study to determine whether these environmental risk factors are related to cognitive decline, stroke and other health outcomes; and (3) disseminate the environmental datasets and public health linkage analyses to end users for decision-making through the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) system. This study directly addresses a public health focus of the NASA Applied Sciences Program, utilization of Earth Sciences products, by addressing issues of environmental health to enhance public health decision-making.