Obesity is a prominent metabolic disease that predisposes individuals to multiple comorbidities, including type 2 diabetes mellitus, cardiovascular diseases, and cancer. Elevated circulating levels of fatty acids contribute to the development of obesity, in part, by targeting the hypothalamus. Palmitate, the most abundant circulating saturated fatty acid, has been demonstrated to dysregulate NAMPT and circadian clock proteins, as well as induce neuroinflammation. These effects ultimately result in hypothalamic dysregulation of feeding behavior and energy homeostasis. NAMPT is the rate-limiting enzyme of the NAD+ salvage pathway and its expression is under the control of the circadian clock. NAD+ produced from NAMPT can modulate the circadian clock, demonstrating bidirectional interactions between circadian and metabolic pathways. Using NPY/AgRP-expressing mHypoE-46 neurons as well as the novel mHypoA-BMAL1-WT/F and mHypoA-BMAL1-KO/F cell lines, we studied whether there were any interactions between NAMPT and the core circadian clock protein BMAL1 in the palmitate-mediated induction of neuroinflammation. We report that palmitate altered Nampt, Bmal1, Per2 and the inflammatory genes Nf-κb, IκBα, Il-6, and Tlr4. Contrary to studies performed with peripheral tissues, the palmitate-mediated induction in Nampt was independent of BMAL1, and basal Nampt levels did not appear to exhibit rhythmic expression. Palmitate-induced downregulation of Bmal1 and Per2 was independent of NAMPT. However, NAMPT and BMAL1 were both involved in the regulation of Nf-κb, IκBα, Il-6, and Tlr4, as NAMPT inhibition resulted in the repression of basal Nf-κb and IκBα and normalized palmitate-mediated increases in Il-6, and Tlr4. On the other hand, BMAL1 deletion repressed basal Nf-κb, but increased basal Il-6. We conclude that NAMPT and BMAL1 do not interact at the transcriptional level in hypothalamic neurons, but are independently involved in the expression of inflammatory genes.
A contributing factor to the development of obesity is the consumption of a diet high in saturated fatty acids, such as palmitate. These fats induce hypothalamic neuroinflammation, which dysregulates neuronal function and induces orexigenic neuropeptide Y (Npy) to promote food intake. An inflammatory cytokine array identified multiple candidates that could mediate palmitate-induced up-regulation of Npy mRNA levels. Of these, visfatin or nicotinamide phosphoribosyltransferase (NAMPT), macrophage migratory inhibitory factor (MIF), and IL-17F were chosen for further study. Direct treatment of the neuropeptide Y/agouti-related peptide (NPY/AgRP)-expressing mHypoE-46 neuronal cell line with the aforementioned cytokines demonstrated that visfatin could directly induce Npy mRNA expression. Preventing the intracellular metabolism of palmitate through long-chain acyl-CoA synthetase (ACSL) inhibition was sufficient to block the palmitate-mediated increase in Npy gene expression.Furthermore, thin-layer chromatography revealed that in neurons, palmitate is readily incorporated into ceramides and defined species of phospholipids. Exogenous C16 ceramide, dipalmitoyl-phosphatidylcholine, and dipalmitoyl-phosphatidylethanolamine were sufficient to significantly induce Npy expression. This study suggests that the intracellular metabolism of palmitate and elevation of metabolites, including ceramide and phospholipids, are responsible for the palmitate-mediated induction of the potent orexigen Npy. Furthermore, this suggests that the regulation of Npy expression is less reliant on inflammatory cytokines per se than palmitate metabolites in a model of NPY/AgRP neurons. These lipid species likely induce detrimental downstream cellular signaling events ultimately causing an increase in feeding, resulting in an overweight phenotype and/or obesity.
Background Asymptomatic diabetes testing may be of limited value for older nursing home residents, but most diabetes guidelines lack upper‐age cutoffs for screening cessation. We evaluated patterns of glycated hemoglobin (HbA1c) and serum blood glucose (SBG) testing among older residents without diabetes in Ontario, Canada. Methods This population‐based retrospective cohort study used provincial health administrative data from ICES to identify older nursing home residents in Ontario without diabetes between January 1, 2015 and December 31, 2018. We examined HbA1c and glucose testing rates overall, by age, sex, and near end‐of‐life. The number of tests needed to identify one case of diabetes (using HbA1c thresholds of 6.5% and 8.0%) were also calculated. Results Among 102,923 older nursing home residents (70.3% women; average age 85.6 ± SD 7.7 years), 46.1% of residents received ≥1 HbA1c test over an average follow‐up period of 2.15 (± SD 1.49) years, and 18.2% of these tested residents received ≥4 HbA1c tests. The crude HbA1c testing rate was 52.6 tests/100 person‐years (95% CI 52.3–52.9). Testing rates among residents aged ≥80 years was 50.7 HbA1c tests/100 person‐years (95% CI 50.4–51.0), and 47.8 tests/100 person‐years (95% CI 46.5–49.0) among residents near end‐of‐life. The number of tests to identify a case of diabetes (HbA1c ≥ 6.5%) was 44, while the number of tests to identify a case of actionable diabetes (HbA1c ≥ 8%) was 310. Less than 1% of residents with an HbA1c test met criteria for actionable diabetes. Conclusions Nursing home residents without diabetes receive frequent diabetes testing, with high testing rates even in residents over 80 years old and residents near end‐of‐life. The high number of tests needed to identify a case of actionable diabetes highlights the urgent need to re‐evaluate diabetes testing practices in nursing homes.
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