Hyperglycemia compensates for diet-induced insulin resistance in liver and skeletal muscle of rats.

High-fat and high-sucrose diets increase the contribution of gluconeogenesis to glucose appearance (glc R(a)) under basal conditions. They also reduce insulin suppression of glc R(a) and insulin-stimulated muscle glycogen synthesis under euglycemic, hyperinsulinemic conditions. The purpose of the present study was to determine whether these impairments influence liver and muscle glycogen synthesis under hyperglycemic, hyperinsulinemic conditions. Male rats were fed a high-sucrose, high-fat, or low-fat, starch control diet for either 1 (n = 5-7/group) or 5 wk (n = 5-6/group). Studies involved two 90-min periods. During the first, a basal period (BP), [6-3H]glucose was infused. In the second, a hyperglycemic period (HP), [6-3H]glucose, [6-14C]glucose, and unlabeled glucose were infused. Plasma glucose (BP: 111.2 +/- 1.5 mg/dl; HP: 172.3 +/- 1.5 mg/dl), insulin (BP: 2.5 +/- 0.2 ng/ml; HP: 4.9 +/- 0.3 ng/ml), and glucagon (BP: 81.8 +/- 1.6 ng/l; HP: 74.0 +/- 1.3 ng/l) concentrations were not significantly different among diet groups or with respect to time on diet. There were no significant differences among groups in the glucose infusion rate (mg x kg(-1) x min(-1)) necessary to maintain arterial glucose concentrations at approximately 170 mg/dl (pooled average: 6.4 +/- 0.8 at 1 wk; 6.4 +/- 0.7 at 5 wk), percent suppression of glc R(a) (44.4 +/- 7.8% at 1 wk; 63.2 +/- 4.3% at 5 wk), tracer-estimated net liver glycogen synthesis (7.8 +/- 1.3 microg x g liver(-1) x min(-1) at 1 wk; 10.5 +/- 2.2 microg x g liver(-1) x min(-1) at 5 wk), indirect pathway glycogen synthesis (3.7 +/- 0.9 microg x g liver(-1) x min(-1) at 1 wk; 3.4 +/- 0.9 microg x g liver(-1) x min(-1) at 5 wk), or tracer-estimated net muscle glycogenesis (1.0 +/- 0.3 microg x g muscle(-1) x min(-1) at 1 wk; 1.6 +/- 0.3 microg x g muscle(-1) x min(-1) at 5 wk). These data suggest that hyperglycemia compensates for diet-induced insulin resistance in both liver and skeletal muscle.

Increased pyruvate flux capacities account for diet-induced increases in gluconeogenesis in vitro.

High-fat (HF) and high-sucrose (SU) diets increase gluconeogenesis. The present study was designed to determine the contributions of pyruvate dehydrogenase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate kinase fluxes to this accelerated gluconeogenesis (GNEO) in the absence and presence of fatty acids. Male Sprague-Dawley rats were fed an HF, SU, or starch (ST) diet for 1 wk, and hepatocytes or mitochondria were isolated. In the absence of palmitate, the tracer estimated rates of GNEO (nmol. min(-1). mg(-1)) were elevated in hepatocytes isolated from SU (32.3 +/- 1.8) and HF (35.4 +/- 1.8) vs. ST (22.8 +/- 1.5). Pyruvate carboxylase and PEPCK flux rates (nmol. min(-1). mg(-1)) were increased in the SU (47.5 +/- 2.2 and 34.8 +/- 1.5) and HF (49.4 +/- 1.8 and 38.2 +/- 1.8) groups compared with the ST group (32.8 +/- 3.2 and 44.3 +/- 2.0). Palmitate (250-1,000 microM) stimulation of these fluxes was not significantly different among groups. Bromopalmitate, an inhibitor of fat oxidation, abolished differences in GNEO, pyruvate carboxylase, and PEPCK fluxes in HF and SU vs. ST. In isolated mitochondria, pyruvate carboxylation and palmitoyl carnitine oxidation were not significantly different among groups. The results of this study suggest that the increased gluconeogenic flux observed with HF and SU diets is associated with an increased pyruvate flux through pyruvate carboxylase and PEPCK. Moreover, the ability of bromopalmitate to normalize gluconeogenic fluxes suggests that endogenous fatty acids contribute to diet-induced increases in GNEO.

Inherent capacity for lipogenesis or dietary fat retention is not increased in obesity-prone rats.

Obesity results from positive energy balance and, perhaps, abnormalities in lipid and glycogen metabolism. The purpose of this study was to determine whether differences in lipogenesis, retention of dietary fat, and/or glycogenesis influenced susceptibility to dietary obesity. After 1 wk of free access to a high-fat diet (HFD; 45% fat by energy) rats were separated on the basis of 1 wk body weight gain into obesity-prone (OP; > or =48 g) or obesity-resistant groups (OR; < or =40 g). Rats were either studied at this time (OR1, OP1) or continued on the HFD for an additional 4 wk (OR5, OP5). Weight gain and energy intake were greater (P < or = 0.05) in OP vs. OR at both 1 (53 +/- 2 vs. 34 +/- 1 g; 892 +/- 27 vs. 755 +/- 14 kcal) and 5 (208 +/- 7 vs. 170 +/- 7 g; 4,484 +/- 82 vs. 4,008 +/- 72 kcal) wk, respectively. Rats were injected with (3)H(2)O and were either provided free access to an HFD meal containing labeled fatty acids (fed; n = 10 or 11/group) or were fasted (n = 10/group) overnight. The amount of food or (14)C tracer eaten overnight was equivalent between OP and OR rats. In liver, the fraction of (3)H retained in glycogen or lipid was not significantly different between OR and OP groups. Retention of dietary fat in the liver was not increased in OP rats. In adipose tissue, retention of (3)H was approximately 49% greater (P < or = 0.05) in OP1 vs. OR1 and approximately 30% greater in OP5 vs. OR5, but retention of dietary fat was not elevated in OP vs. OR. At the same time, fat pad weight (sum of epididymal, retroperitoneal, mesenteric) was 49% greater in OP1 rats vs. OR1 rats and 65% greater in OP5 vs. OR5 rats (P < or = 0.05). Thus a greater capacity for lipogenesis or retention of dietary fat does not appear to be included in the OP phenotype. The characteristic increase in energy intake associated with OP rats appears to be necessary and critical to accelerated weight and fat gain.

Fat oxidation, lipolysis, and free fatty acid cycling in obesity-prone and obesity-resistant rats.

Defects in fat metabolism may contribute to the development of obesity, but what these defects are and where they occur in the feeding/fasting cycle are unknown. In the present study, basal fat metabolism was characterized using a high-fat diet (HFD)-induced model of obesity development. Male rats consumed a HFD (45% fat, 35% carbohydrate) ad libitum for either 1 or 5 wk (HFD1 or HFD5). After 1 wk on the HFD, rats were separated on the basis of body weight gain into obesity-prone (OP, > or =48 g) or obesity-resistant (OR,