Altered feeding differentially regulates circadian rhythms and energy metabolism in liver and muscle of rats.

Energy metabolism follows a diurnal pattern responding to the light/dark cycle and food availability. This study investigated the impact of restricting feeding to the daylight hours and feeding a high fat diet on circadian clock (bmal1, dbp, tef and e4bp4) and metabolic (pepck, fas, ucp3, pdk4) gene expression and markers of energy metabolism in muscle and liver of rats. The results show that in chow-fed rats switched to daylight feeding, the peak diurnal expression of genes in liver was shifted by 6-12h while expression of these genes in muscle remained in a similar phase to rats feeding ad libitum. High fat feeding during the daylight hours had limited effect on clock gene expression in liver or muscle but shifted the peak expression of metabolic genes (pepck, fas) in liver by 6-12h. The differential effects of daylight feeding on gene and protein expression in muscle and liver were accompanied by an 8% reduction in whole body energy expenditure, a 20-30% increased glycogen content during the light phase in muscle of day-fed rats and increased adipose tissue deposition per gram food consumed. These data demonstrate that a mismatch of feeding and light/dark cycle disrupts tissue metabolism in muscle with significant consequences for whole body energy homeostasis.

The Hunt for Baby Melanomas: A Prospective Study of the Dermoscopy Features on 100 Small Melanoma Cases with in Vivo Surface Diameters up to a Maximum of 6 mm.

Introduction: Early diagnosis can improve melanoma prognosis. Dermoscopy can enhance early melanoma recognition. Objectives: Examine the dermoscopy features of early melanoma up to a maximum surface diameter of 6 mm. Methods: Consecutive melanoma cases were collected from two medical practices in Sydney, Australia 2019-2021. Dermoscopy features were recorded for melanomas by maximum surface diameter, to the nearest 0.1 mm, to a limit of 6 mm. Results: Total cases numbered 100; with males (N = 48) and females (N = 52), melanoma in situ (MIS, N = 96) and invasive (N = 4). The most frequent anatomic sites on both males and females were back (males N = 20, females N = 16) then knee or leg (males N = 8, females N = 12). Minimum respective MIS diameters for males/females was 1.2/2.0 mm and for invasive cases 2.0/3.4 mm. Highest frequency dermoscopy features were: light brown, dark brown, gray and asymmetric melanoma shape. Brown pigment in hair follicles were more frequent on legs compared to other anatomic sites (odds ratio [OR] 14.6; 95% CI 1.29-165.17, P 0.03). Pseudopods were substantially increased in frequency comparing diameters less than 4 mm with 4 up to 6 mm (OR 8.81; 95% CI 1.05-73.9, P 0.004). Structureless area cases recorded increased gray (OR 7.08; 95% CI 1.61-31.11, P=0.01). Melanomas with edge angulation were noted in 20%-50% of cases across diameters 1-6 mm, less frequent were pigmented circles and polygons. Conclusions: Watch out! MIS presented with a surface diameter of just 1.2 mm and invasive melanoma 2.5 mm. Pseudopods were a strong clue to melanomas with a surface diameter less than 5mm. We found melanomas on leg sites displayed more frequent pigmented hair follicles.

Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis.

Growth factor receptor bound (Grb)10 and Grb14 are closely related adaptor proteins that bind directly to the insulin receptor (IR) and regulate insulin-induced IR tyrosine phosphorylation and signaling to IRS-1 and Akt. Grb10- and Grb14-deficient mice both exhibit improved whole-body glucose homeostasis as a consequence of enhanced insulin signaling and, in the case of the former, altered body composition. However, the combined physiological role of these adaptors has remained undefined. In this study we utilize compound gene knockout mice to demonstrate that although deficiency in one adaptor can enhance insulin-induced IRS-1 phosphorylation and Akt activation, insulin signaling is not increased further upon dual ablation of Grb10 and Grb14. Context-dependent limiting mechanisms appear to include IR hypophosphorylation and decreased IRS-1 expression. In addition, the compound knockouts exhibit an increase in lean mass comparable to Grb10-deficient mice, indicating that this reflects a regulatory function specific to Grb10. However, despite the absence of additive effects on insulin signaling and body composition, the double-knockout mice are protected from the impaired glucose tolerance that results from high-fat feeding, whereas protection is not observed with animals deficient for individual adaptors. These results indicate that, in addition to their described effects on IRS-1/Akt, Grb10 and Grb14 may regulate whole-body glucose homeostasis by additional mechanisms and highlight these adaptors as potential therapeutic targets for amelioration of the insulin resistance associated with type 2 diabetes.

Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species dependent: potent tissue-specific effects of medium-chain fatty acids.

OBJECTIVE: Medium-chain fatty acids (MCFAs) have been reported to be less obesogenic than long-chain fatty acids (LCFAs); however, relatively little is known regarding their effect on insulin action. Here, we examined the tissue-specific effects of MCFAs on lipid metabolism and insulin action. RESEARCH DESIGN AND METHODS: C57BL6/J mice and Wistar rats were fed either a low-fat control diet or high-fat diets rich in MCFAs or LCFAs for 4-5 weeks, and markers of mitochondrial oxidative capacity, lipid levels, and insulin action were measured. RESULTS: Mice fed the MCFA diet displayed reduced adiposity and better glucose tolerance than LCFA-fed animals. In skeletal muscle, triglyceride levels were increased by the LCFA diet (77%, P < 0.01) but remained at low-fat diet control levels in the MCFA-fed animals. The LCFA diet increased (20-50%, P < 0.05) markers of mitochondrial metabolism in muscle compared with low-fat diet-fed controls; however; the increase in oxidative capacity was substantially greater in MCFA-fed animals (50-140% versus low-fat-fed controls, P < 0.01). The MCFA diet induced a greater accumulation of liver triglycerides than the LCFA diet, likely due to an upregulation of several lipogenic enzymes. In rats, isocaloric feeding of MCFA or LCFA high-fat diets induced hepatic insulin resistance to a similar degree; however, insulin action was preserved at the level of low-fat diet-fed controls in muscle and adipose from MCFA-fed animals. CONCLUSIONS: MCFAs reduce adiposity and preserve insulin action in muscle and adipose, despite inducing steatosis and insulin resistance in the liver. Dietary supplementation with MCFAs may therefore be beneficial for preventing obesity and peripheral insulin resistance.

Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents.

A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including (14)C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, beta-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet-fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1alpha, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.