Fenretinide is a synthetic retinoid that is being tested in clinical trials for the treatment of breast cancer and insulin resistance, but its mechanism of action has been elusive. Recent in vitro data indicate that fenretinide inhibits dihydroceramide desaturase, an enzyme involved in the biosynthesis of lipotoxic ceramides that antagonize insulin action. Because of this finding, we assessed whether fenretinide could improve insulin sensitivity and glucose homeostasis in vitro and in vivo by controlling ceramide production. The effect of fenretinide on insulin action and the cellular lipidome was assessed in a number of lipid-challenged models including cultured myotubes and isolated muscles strips incubated with exogenous fatty acids and mice fed a high-fat diet. Insulin action was evaluated in the various models by measuring glucose uptake or disposal and the activation of Akt/PKB, a serine/threonine kinase that is obligate for insulin-stimulated anabolism. The effects of fenretinide on cellular lipid levels were assessed by LC-MS/MS. Fenretinide negated lipid-induced insulin resistance in each of the model systems assayed. Simultaneously, the drug depleted cells of ceramide, while promoting the accumulation of the precursor dihydroceramide, a substrate for the reaction catalyzed by Des1. These data suggest that fenretinide improves insulin sensitivity, at least in part, by inhibiting Des1 and suggest that therapeutics targeting this enzyme may be a viable therapeutic means for normalizing glucose homeostasis in the overweight and diabetic.

Ceramide is a sphingolipid that serves as an important second messenger in an increasing number of stress-induced pathways. Ceramide has long been known to affect the mitochondria, altering both morphology and physiology. We sought to assess the impact of ceramide on skeletal muscle mitochondrial structure and function. A primary observation was the rapid and dramatic division of mitochondria in ceramide-treated cells. This effect is likely to be a result of increased Drp1 (dynamin-related protein 1) action, as ceramide increased Drp1 expression and Drp1 inhibition prevented ceramide-induced mitochondrial fission. Further, we found that ceramide treatment reduced mitochondrial O2 consumption (i.e. respiration) in cultured myotubes and permeabilized red gastrocnemius muscle fibre bundles. Ceramide treatment also increased H2O2 levels and reduced Akt/PKB (protein kinase B) phosphorylation in myotubes. However, inhibition of mitochondrial fission via Drp1 knockdown completely protected the myotubes and fibre bundles from ceramide-induced metabolic disruption, including maintained mitochondrial respiration, reduced H2O2 levels and unaffected insulin signalling. These data suggest that the forced and sustained mitochondrial fission that results from ceramide accrual may alter metabolic function in skeletal muscle, which is a prominent site not only of energy demand (via the mitochondria), but also of ceramide accrual with weight gain.

Introduction: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain.Methods: RNA‐seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes.Results: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia.Discussion: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.

The clinical benefit of ketosis has historically and almost exclusively centered on neurological conditions, lending insight into how ketones alter mitochondrial function in neurons. However, there is a gap in our understanding of how ketones influence mitochondria within skeletal muscle cells. The purpose of this study was to elucidate the specific effects of β-hydroxybutyrate (β-HB) on muscle cell mitochondrial physiology. In addition to increased cell viability, murine myotubes displayed beneficial mitochondrial changes evident in reduced H₂O₂ emission and less mitochondrial fission, which may be a result of a β-HB-induced reduction in ceramides. Furthermore, muscle from rats in sustained ketosis similarly produced less H₂O₂ despite an increase in mitochondrial respiration and no apparent change in mitochondrial quantity. In sum, these results indicate a general improvement in muscle cell mitochondrial function when β-HB is provided as a fuel.

Because low-carbohydrate diets are effective strategies to improve insulin resistance, the hallmark of type 2 diabetes, the purpose of reporting these clinical cases was to reveal the meaningful changes observed in 90 days of low-carbohydrate (LC) ketogenic dietary intervention in female type 2 diabetics aged 18-45. Eleven women (BMI 36.3 kg/m²) who were recently diagnosed with type 2 diabetes based on HbA1c over 6.5% (8.9%) volunteered to participate in an intensive dietary intervention to limit dietary carbohydrates to under 30 grams daily for 90 days. The main outcome was to determine the degree of change in HbA1c, while secondary outcomes included body weight, blood pressure, and blood lipids. The volunteers lost significant weight (85.7±3.2kg to 76.7±2.8kg) and lowered systolic (134.0±1.6 to 123.3±1.1mmHg) and diastolic (89.9±1.3 to 82.6±1.0mmHg) blood pressure. HbA1c dropped to 5.6%. Most blood lipids were significantly altered, including HDL cholesterol (43.1±4.4 to 52.3±3.3mg/dl), triglycerides (177.0±19.8 to 92.1±8.7mg/dl), and the TG : HDL ratio (4.7±0.8 to 1.9±0.2). LDL cholesterol was not significantly different. AST and ALT, plasma markers of liver health, were reported for eight patients and revealed no significant changes. These findings indicate that a short-term intervention emphasizing protein and fat at the expense of dietary carbohydrate functionally reversed the diabetes diagnosis, as defined by HbA1c. Furthermore, the intervention lowered body weight and blood pressure, while eliciting favorable changes in blood lipids.