Growth hormone inhibits hepatic de novo lipogenesis in adult mice

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients

Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise

Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity

HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism

Clear cell renal cell carcinoma (ccRCC) is histologically defined by its lipid and glycogen-rich cytoplasmic deposits. Alterations in the VHL tumor suppressor stabilizing the hypoxiainducible factors (HIFs) are the most prevalent molecular features of clear cell tumors. The significance of lipid deposition remains undefined. We describe the mechanism of lipid deposition in ccRCC by identifying the rate-limiting component of mitochondrial fatty acid transport, carnitine palmitoyltransferase 1A (CPT1A), as a direct HIF target gene. CPT1A is repressed by HIF1 and HIF2, reducing fatty acid transport into the mitochondria, and forcing fatty acids to lipid droplets for storage. Droplet formation occurs independent of lipid source, but only when CPT1A is repressed. Functionally, repression of CPT1A is critical for tumor formation, as elevated CPT1A expression limits tumor growth. In human tumors, CPT1A expression and activity are decreased versus normal kidney; and poor patient outcome associates with lower expression of CPT1A in tumors in TCGA. Together, our studies identify HIF control of fatty acid metabolism as essential for ccRCC tumorigenesis

Impairments in oxidative glucose metabolism in epilepsy and metabolic treatments thereof

There is mounting evidence that oxidative glucose metabolism is impaired in epilepsy and recent work has further characterized the metabolic mechanisms involved. In healthy people eating a traditional diet, including carbohydrates, fats and protein, the major energy substrate in brain is glucose. Cytosolic glucose metabolism generates small amounts of energy, but oxidative glucose metabolism in the mitochondria generates most ATP, in addition to biosynthetic precursors in cells. Energy is crucial for the brain to signal "normally," while loss of energy can contribute to seizure generation by destabilizing membrane potentials and signaling in the chronic epileptic brain. Here we summarize the known biochemical mechanisms that contribute to the disturbance in oxidative glucose metabolism in epilepsy, including decreases in glucose transport, reduced activity of particular steps in the oxidative metabolism of glucose such as pyruvate dehydrogenase activity, and increased anaplerotic need. This knowledge justifies the use of alternative brain fuels as sources of energy, such as ketones, TCA cycle intermediates and precursors as well as even medium chain fatty acids and triheptanoin

Triheptanoin alters [U- 13 C 6 ]-glucose incorporation into glycolytic intermediates and increases TCA cycling by normalizing the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase in a chronic epilepsy mouse model

Triheptanoin is anticonvulsant in several seizure models. Here, we investigated changes in glucose metabolism by triheptanoin interictally in the chronic stage of the pilocarpine mouse epilepsy model. After injection of [U- C ]-glucose (i.p.), enrichments of C in intermediates of glycolysis and the tricarboxylic acid (TCA) cycle were quantified in hippocampal extracts and maximal activities of enzymes in each pathway were measured. The enrichment of C glucose in plasma was similar across all groups. Despite this, we observed reductions in incorporation of C in several glycolytic intermediates compared to control mice suggesting glucose utilization may be impaired and/or glycogenolysis increased in the untreated interictal hippocampus. Triheptanoin prevented the interictal reductions of C incorporation in most glycolytic intermediates, suggesting it increased glucose utilization or – as an additional astrocytic fuel – it decreased glycogen breakdown. In the TCA cycle metabolites, the incorporation of C was reduced in the interictal state. Triheptanoin restored the correlation between C enrichments of pyruvate relative to most of the TCA cycle intermediates in “epileptic” mice. Triheptanoin also prevented the reductions of hippocampal pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase activities. Decreased glycogen breakdown and increased glucose utilization and metabolism via the TCA cycle in epileptogenic brain areas may contribute to triheptanoin's anticonvulsant effects

Tridecanoin is anticonvulsant, antioxidant, and improves mitochondrial function

The hypothesis that chronic feeding of the triglycerides of octanoate (trioctanoin) and decanoate (tridecanoin) in "a regular non-ketogenic diet" is anticonvulsant was tested and possible mechanisms of actions were subsequently investigated. Chronic feeding of 35E% of calories from tridecanoin, but not trioctanoin, was reproducibly anticonvulsant in two acute CD1 mouse seizure models. The levels of beta-hydroxybutyrate in plasma and brain were not significantly increased by either treatment relative to control diet. The respective decanoate and octanoate levels are 76 µM and 33 µM in plasma and 1.17 and 2.88 nmol/g in brain. Tridecanoin treatment did not alter the maximal activities of several glycolytic enzymes, suggesting that there is no reduction in glycolysis contributing to anticonvulsant effects. In cultured astrocytes, 200 µM of octanoic and decanoic acids increased basal respiration and ATP turnover, suggesting that both medium chain fatty acids are used as fuel. Only decanoic acid increased mitochondrial proton leak which may reduce oxidative stress. In mitochondria isolated from hippocampal formations, tridecanoin increased respiration linked to ATP synthesis, indicating that mitochondrial metabolic functions are improved. In addition, tridecanoin increased the plasma antioxidant capacity and hippocampal mRNA levels of heme oxygenase 1, and FoxO1

Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy

We hypothesize that endothelial-specific thioredoxin-interacting protein knock-out (EC-TXNIP KO) mice will be more resistant to the neurovascular damage (hemorrhagic-transformation-HT) associated with hyperglycemia (HG) in embolic stroke. Adult-male EC-TXNIP KO and wild-type (WT) littermate mice were injected with-streptozotocin (40 mg/kg, i.p.) for five consecutive days to induce diabetes. Four-weeks after confirming HG, mice were subjected to embolic middle cerebral artery occlusion (eMCAO) followed by tissue plasminogen activator (tPA)-reperfusion (10 mg/kg at 3 h post-eMCAO). After the neurological assessment, animals were sacrificed at 24 h for neurovascular stroke outcomes. There were no differences in cerebrovascular anatomy between the strains. Infarct size, edema, and HT as indicated by hemoglobin (Hb)-the content was significantly higher in HG-WT mice, with or without tPA-reperfusion, compared to normoglycemic WT mice. Hyperglycemic EC-TXNIP KO mice treated with tPA tended to show lower Hb-content, edema, infarct area, and less hemorrhagic score compared to WT hyperglycemic mice. EC-TXNIP KO mice showed decreased expression of inflammatory mediators, apoptosis-associated proteins, and nitrotyrosine levels. Further, vascular endothelial growth factor-A and matrix-metalloproteinases (MMP-9/MMP-3), which degrade junction proteins and increase blood-brain-barrier permeability, were decreased in EC-TXNIP KO mice. Together, these findings suggest that vascular-TXNIP could be a novel therapeutic target for neurovascular damage after stroke