Chronic high corticosterone with voluntary corn oil ingestion induces significant body weight gain in mice.

Corticosterone (CORT) is a powerful regulator of energy metabolism, and chronically high CORT levels cause obesity and diabetes in mice. It is reported that a chronically high CORT level changes food preference, increasing the intake of comfort foods such as fatty foods. Previously, we demonstrated that unlike a high fat diet, voluntary ingestion of 100% pure corn oil increased energy expenditure and thermogenesis through the activation of the interscapular brown adipose tissue (IBAT). In the present study, we investigated whether chronically high CORT affected corn oil intake, energy expenditure, and body weight gain. We delivered CORT to mice via water bottles and placed corn oil in a separate drinking bottle in the home cage. Voluntary corn oil ingestion with CORT induced significant body weight gain, while corn oil ingestion or CORT alone had a modest effect. CORT increased corn oil intake without reducing chow intake, which further increased the total daily caloric intake. CORT suppressed mRNA related to thermogenesis in IBAT. In the hypothalamus, CORT upregulated mRNA expression of the orexigenic neuropeptide, agouti-related protein. These data suggest that chronically high CORT might increase the desire to consume dietary fat, suppressing BAT function, thereby causing obesity.

Voluntary Corn Oil Ingestion Increases Energy Expenditure and Interscapular UCP1 Expression Through the Sympathetic Nerve in C57BL/6 Mice.

SCOPE: Previously, it has been found that corn oil ingestion activates both the gustatory system and brain reward system, stimulating motivation for eating. In the present study, the effect of voluntary corn oil ingestion on body weight gain and energy metabolism in mice is investigated. METHODS AND RESULTS: Voluntary corn oil ingestion with normal chow feeding does not lead to higher body weight than that of only the chow-fed control group. Mice that ingested corn oil have a higher total caloric intake and energy expenditure than did mice in the control group. Further, voluntary corn oil ingestion significantly upregulates Ucp1 mRNA and protein in interscapular brown adipose tissue (IBAT). Finally, the sympathetic nerve connected to IBAT was surgically transacted, then the body weight is measured for 8 weeks. IBAT sympathetic nerve transection surgery does not affect the body weight gain and food intake; however, when mice ingested corn oil, it induces significant body weight gain without changing the total caloric intake. IBAT sympathetic nerve transection surgery significantly suppresses UCP1 upregulation by corn oil ingestion. CONCLUSION: The present data suggest that corn oil ingestion activates IBAT through the sympathetic nerve, upregulating UCP1 expression and increasing energy expenditure.

CD36 is essential for endurance improvement, changes in whole-body metabolism, and efficient PPAR-related transcriptional responses in the muscle with exercise training.

Although circulating fatty acids are utilized as energy substrates, they also function as ligands to the peroxisome-proliferator activated receptors (PPARs), a family of fatty acid sensing transcription factors. Exercise training leads to various adaptations in the muscle such as elevation of glycogen content, mitochondrial number as well as upregulation of fatty acid uptake and utilization through downstream transcriptional adaptations. In line with this, CD36 has been shown to be critical in controlling fatty acid uptake and consequently, fatty acid oxidation. We show that exercise training could not ameliorate impaired endurance performance in CD36 KO mice despite intact adaptations in muscle glycogen storage and mitochondrial function. Changes in whole-body metabolism at rest and during exercise were also suppressed in these animals. Furthermore, there was inefficient upregulation of PPAR and PPAR-related exercise-responsive genes with chronic training in CD36 KO mice despite normal upregulation of Pgc1a and mitochondrial genes. Our findings supplement previous observations and emphasize the importance of CD36 in endurance performance, energy production and efficient downstream transcriptional regulation by PPARs.

Combined pharmacological activation of AMPK and PPARδ potentiates the effects of exercise in trained mice.

The combined activation of the cellular energy sensor AMP-activated protein kinase (AMPK) and the nuclear transcription factor peroxisome proliferator-activated receptor delta (PPARδ) has been demonstrated to improve endurance and muscle function by mimicking the effects of exercise training. However, their combined pharmacological activation with exercise training has not been explored. Balb/c mice were trained on a treadmill and administered both the AMPK activator AICAR and the PPARδ agonist GW0742 for 4 weeks. AICAR treatment potentiated endurance, but the combination of AICAR and GW0742 further potentiated endurance and increased all running parameters significantly relative to exercised and nonexercised groups (138-179% and 355% increase in running time, respectively). Despite the lack of change in basal whole-body metabolism, a significant shift to fat as the main energy source with a decline in carbohydrate utilization was observed upon indirect calorimetry analysis at the period near exhaustion. Increased energy substrates before exercise, and elevated muscle nonesterified fatty acids (NEFA) and elevated muscle glycogen at exhaustion were observed together with increased PDK4 mRNA expression. Citrate synthase activity was elevated in AICAR-treated groups, while PGC-1α protein level tended to be increased in GW0742-treated groups. At exhaustion, Pgc1a was robustly upregulated together with Pdk4, Cd36, and Lpl in the muscle. A robust upregulation of Pgc1a and a downregulation in Chrebp were observed in the liver. Our data show that combined pharmacological activation of AMPK and PPARδ potentiates endurance in trained mice by transcriptional changes in muscle and liver, increased available energy substrates, delayed hypoglycemia through glycogen sparing accompanied by increased NEFA availability, and improved substrate shift from carbohydrate to fat.

Hepatocyte ß-Klotho regulates lipid homeostasis but not body weight in mice.

ß-Klotho (ß-Kl), a transmembrane protein expressed in the liver, pancreas, adipose tissues, and brain, is essential for feedback suppression of hepatic bile acid synthesis. Because bile acid is a key regulator of lipid and energy metabolism, we hypothesized potential and tissue-specific roles of ß-Kl in regulating plasma lipid levels and body weight. By crossing ß-kl(-/-) mice with newly developed hepatocyte-specific ß-kl transgenic (Tg) mice, we generated mice expressing ß-kl solely in hepatocytes (ß-kl(-/-)/Tg). Gene expression, metabolomic, and in vivo flux analyses consistently revealed that plasma level of cholesterol, which is over-excreted into feces as bile acids in ß-kl(-/-), is maintained in ß-kl(-/-) mice by enhanced de novo cholesterogenesis. No compensatory increase in lipogenesis was observed, despite markedly decreased plasma triglyceride. Along with enhanced bile acid synthesis, these lipid dysregulations in ß-kl(-/-) were completely reversed in ß-kl(-/-)/Tg mice. In contrast, reduced body weight and resistance to diet-induced obesity in ß-kl(-/-) mice were not reversed by hepatocyte-specific restoration of ß-Kl expression. We conclude that ß-Kl in hepatocytes is necessary and sufficient for lipid homeostasis, whereas nonhepatic ß-Kl regulates energy metabolism. We further demonstrate that in a condition with excessive cholesterol disposal, a robust compensatory mechanism maintains cholesterol levels but not triglyceride levels in mice.