Casitas b-lineage lymphoma-deficient mice are pretected against high-fat diet-induuced obesity and insulin resistance

Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity involved in regulating the degradation of receptor tyrosine kinases. We have recently reported that c-Cbl^–/– mice exhibit a lean phenotype and enhanced peripheral insulin action likely due to elevated energy expenditure. In the study reported here, we examined the effect of a high-fat diet on energy homeostasis and glucose metabolism in these animals. When c-Cbl^–/– mice were fed a high-fat diet for 4 weeks, they maintained hyperphagia, higher whole-body oxygen consumption (27%), and greater activity (threefold) compared with wild-type animals fed the same diet. In addition, the activity of several enzymes involved in mitochondrial fat oxidation and the phosphorylation of acetyl CoA carboxylase was significantly increased in muscle of high-fat–fed c-Cbl–deficient mice, indicating a greater capacity for fat oxidation in these animals. As a result of these differences, fat-fed c-Cbl^–/– mice were 30% leaner than wild-type animals and were protected against high-fat diet–induced insulin resistance. These studies are consistent with a role for c-Cbl in regulating nutrient partitioning in skeletal muscle and emphasize the potential of c-Cbl as a therapeutic target in the treatment of obesity and type 2 diabetes.

Does perinatal ω-3 polyunsaturated fatty acid deficiency increase appetite signaling?

Objective: To investigate the effect of maternal dietary ω-3 polyunsaturated fatty acid (PUFA) deficiency and repletion on food appetite signaling.
Research Methods and Procedures: Sprague-Dawley rat dams were maintained on diets either supplemented with (CON) or deficient in (DEF) ω-3 PUFA. All offspring were raised on the maternal diet until weaning. After weaning, two groups remained on the respective maternal diet (CON and DEF groups), whereas a third group, born of dams fed the DEF diet, were switched to the CON diet (REC). Experiments on food intake began when the male rats reached 16 weeks of age. Food intake was stimulated either by a period of food restriction, by blocking glucose utilization (by 2-deoxyglucose injection), or by blocking β-oxidation of fatty acids (by β-mercaptoacetate injection).
Results: DEF animals consumed more than CON animals in response to all stimuli, with the greatest difference (1.9-fold) demonstrated following administration of 2-deoxyglucose. REC animals also consumed more than CON animals in response to food restriction and 2-deoxyglucose but not to β-mercaptoacetate.
Discussion: These findings indicate that supply of ω-3 PUFA, particularly during the perinatal period, plays a role in the normal development of mechanisms controlling food intake, especially glucoprivic (i.e. reduced glucose availability) appetite signaling. Dietary repletion of ω-3 PUFA from 3 weeks of age restored intake responses to fatty acid metabolite signaling but did not reverse those in response to food restriction or glucoprivic stimuli.

Brain neuropeptide Y and CCK and peripheral adipokine receptors : temporal response in obesity induced by palatable diet

Objective:
Palatable food disrupts normal appetite regulation, which may contribute to the etiology of obesity. Neuropeptide Y (NPY) and cholecystokinin play critical roles in the regulation of food intake and energy homeostasis, while adiponectin and carnitine palmitoyltransferase (CPT) are important for insulin sensitivity and fatty acid oxidation. This study examined the impact of short- and long-term consumption of palatable high-fat diet (HFD) on these critical metabolic regulators.

Methods:
Male C57BL/6 mice were exposed to laboratory chow (12% fat), or cafeteria-style palatable HFD (32% fat) for 2 or 10 weeks. Body weight and food intake were monitored throughout. Plasma leptin, hypothalamic NPY and cholecystokinin, and mRNA expression of leptin, adiponectin, their receptors and CPT-1, in fat and muscles were measured.

Results:
Caloric intake of the palatable HFD group was 2–3 times greater than control, resulting in a 37% higher body weight. Fat mass was already increased at 2 weeks; plasma leptin concentrations were 2.4 and 9 times higher than control at 2 and 10 weeks, respectively. Plasma adiponectin was increased at 10 weeks. Muscle adiponectin receptor 1 was increased at 2 weeks, while CPT-1 mRNA was markedly upregulated by HFD at both time points. Hypothalamic NPY and cholecystokinin content were significantly decreased at 10 weeks.

Conclusion:
Palatable HFD induced hyperphagia, fat accumulation, increased adiponectin, leptin and muscle fatty acid oxidation, and reduced hypothalamic NPY and cholecystokinin. Our data suggest that the adaptive changes in hypothalamic NPY and muscle fatty acid oxidation are insufficient to reverse the progress of obesity and metabolic consequences induced by a palatable HFD.

Specific role of dietary fat in modifying cardiovascular and locomotor activity 24-h rhythms

Meal-fed conscious rabbits normally exhibit postprandial elevation in blood pressure, heart rate (HR) and locomotor activity, which is abolished by consumption of a high-fat diet (HFD). Here, we assessed whether the cardiovascular changes are attributable to the increased caloric intake due to greater fat content or to hyperphagia. Rabbits were meal-fed during the baseline period then maintained on either an ad libitum normal fat diet (NFD) or ad libitum HFD for 2 weeks. Blood pressure, HR and locomotor activity were measured daily by radio-telemetry alongside food intake and body weight. Caloric intake in rabbits given a NFD ad libitum rose 50% from baseline but there were no changes in cardiovascular parameters. By contrast, HR increased by 10% on the first day of the ad libitum HFD (p<0.001) prior to any change in body weight while blood pressure increased 7% after 4d (p<0.01) and remained elevated. Baseline 24-h patterns of blood pressure and HR were closely associated with mealtime, characterised by afternoon peaks and morning troughs. When the NFD was changed from meal-fed to ad libitum, blood pressure and HR did not change but afternoon activity levels decreased (p<0.05). By contrast, after 13d ad libitum HFD, morning HR, blood pressure and activity increased by 20%, 8% and 71%, respectively. Increased caloric intake specifically from fat, but not as a result of hyperphagia, appears to directly modulate cardiovascular homeostasis and circadian patterns, independent of white adipose tissue accumulation.