Role of insulin receptors in the changing metabolism of adipose tissue during pregnancy and lactation in the rat.

Changes in the volume, the rates of fatty acid synthesis and synthesis of the glycerol moiety of acylglycerols, the activity of lipoprotein lipase, and the number and affinity of insulin receptors of adipocytes, and concentrations of serum insulin, prolactin and progesterone were determined in virgin rats and in rats at various stages of pregnancy and lactation. Changes in the metabolic activities of adipose tissue appeared to be synchronized and primarily comprised a marked decrease in anabolic activity around parturition. In contrast, the number of insulin receptors (Kd 1.5 nM) per adipocyte doubled during pregnancy before returning to normal values around parturition. It is postulated that the increase in the number of insulin receptors is an adaptation to counteract the effects of insulin-antagonistic hormones during pregnancy and that the decrease in the number of receptors is primarily responsible for the loss of anabolic activity around parturition.     

Metabolism of sheep adipose tissue during pregnancy and lactation. Adaptation and regulation.

1. Changes in the mean volume, the rate of fatty acid and acylglycerol glycerol synthesis, the activity of lipoprotein lipase and the numbers and affinities of insulin receptors of subcutaneous adipocytes are reported for sheep at different stages of pregnancy and lactation. In addition, the serum concentrations of insulin, progesterone, prolactin, choriomammotropin, somatotropin, glucose, acetate, L-lactate, glycerol and unesterified fatty acids are reported for these sheep. 2. A switch from lipid accumulation to net lipid mobilization accompanied by a decline in the capacity for lipid synthesis, occurred at the onset of the last third of pregnancy. Net lipid mobilization continued during lactation. 3. The changes that occurred in the serum concentrations of the various hormones listed above are discussed in relation to their possible roles in the modulation of adipose tissue metabolism in sheep during pregnancy and lactation. The observations are compared with those from previous studies on the hormonal control of adipose tissue metabolism in the rat during pregnancy and lactation.     

Phosphatidic acid and phosphatidylinositol labelling in adipose tissue. Relationship to the metabolic effects of insulin and insulin-like agents.

Exposure to phospholipase C increased the incorporation of [32P]Pi into phosphatidate, CMP-phosphatidate and phosphatidylinositol in rat adipose tissue and isolated adipocytes. A similar effect was observed in response to insulin and oxytocin. Theophylline, 3-isobutyl-1-methylxanthine and adenosine deaminase decreased [32P]Pi incorporation, and adenosine and N6-phenylisopropyladenosine reversed these effects. As with insulin, exposure of adipose tissue to phospholipase C stimulated oxidation of glucose, pyruvate and leucine and activated pyruvate dehydrogenase. Oxytocin and adenosine also mimicked the effects of insulin on leucine oxidation and pyruvate dehydrogenase. However, only insulin stimulated glycogen synthase activity, indicating that the regulation of synthase may be achieved by intracellular events distinct from those regulating changes in phospholipid metabolism, sugar transport and mitochondrial enzyme activities. It is postulated that exposure to phospholipase C forms diacylglycerol, which is phosphorylated to yield phosphatidate. The increased labelling of CMP-phosphatidate and phosphatidylinositol results from the conversion of phosphatidate into these lipids. The correlation between the effects of phospholipase C on phosphatidate synthesis and changes in adipose-tissue metabolism suggests the possibility that increased phosphatidate may directly or indirectly produce changes in membrane transport and enzyme activities. The pattern of phospholipid labelling produced by insulin, adenosine and oxytocin suggests that these stimuli may also increase phosphatidate synthesis, and, if so, changes in phospholipid metabolism could account for some of the metabolic actions of these stimuli.     

Peripheral adipose tissue insulin resistance alters lipid composition and function of hippocampal synapses

Compelling evidence indicates that type 2 diabetes mellitus, insulin resistance (IR), and metabolic syndrome are often accompanied by cognitive impairment. However, the mechanistic link between these metabolic abnormalities and CNS dysfunction requires further investigations. Here, we evaluated whether adipose tissue IR and related metabolic alterations resulted in CNS changes by studying synapse lipid composition and function in the adipocyte‐specific ecto‐nucleotide pyrophosphate phosphodiesterase over‐expressing transgenic (AtENPP1‐Tg) mouse, a model characterized by white adipocyte IR, systemic IR, and ectopic fat deposition. When fed a high‐fat diet, AtENPP1‐Tg mice recapitulate essential features of the human metabolic syndrome, making them an ideal model to characterize peripherally induced CNS deficits. Using a combination of gas chromatography and western blot analysis, we found evidence of altered lipid composition, including decreased phospholipids and increased triglycerides (TG) and free fatty acid in hippocampal synaptosomes isolated from high‐fat diet‐fed AtENPP1‐Tg mice. These changes were associated with impaired basal synaptic transmission at the Schaffer collaterals to hippocampal cornu ammonis 1 (CA1) synapses, decreased phosphorylation of the GluN1 glutamate receptor subunit, down‐regulation of insulin receptor expression, and up‐regulation of the free fatty acid receptor 1.

     

Thermogenic and metabolic consequences of thyroid hormone treatment in brown and white adipose tissue

Male rats were treated with triiodothyronine in the drinking water for 12 days. In vitro rates of isoprenaline stimulated lipolysis were significantly greater in brown but not white adipose tissue. Rates of [¹⁴C]glucose incorporation into triacylglycerols were significantly reduced in BAT (brown adipose tissue) and WAT (white adipose tissue) under basal and isoprenaline stimulated conditions, in a second experiment, hyperthyroid animals showed impaired weight gain, despite increased food intake during t9 days' treatment. Energy expenditure on days 5 and 12, and BAT core temperature differences (TBAT - T_CORE) on day 19, were significantly greater than in control animals. Epididymal white fat pad weight was reduced and interscapular brown fat pad weight increased by triiodothyronine treatment.     

Functional atrophy of brown adipose tissue during lactation in mice. Effects of lactation and weaning on mitochondrial GDP binding and uncoupling protein.

The thermogenic activity and capacity of brown adipose tissue were determined in mice during lactation and after weaning. There was a marked fall during lactation in the mitochondrial content of the tissue, and in GDP binding and the specific mitochondrial concentration of uncoupling protein. The lactation-induced functional atrophy of brown adipose tissue was fully reversible after weaning; mitochondrial content and the mitochondrial concentration of uncoupling protein were both restored, although GDP binding was not normalized.     

Integration of lipid metabolism in the mammary gland and adipose tissue by prolactin during lactation

Prolactin deficiency, induced by bromocryptine treatment, brought about reciprocal changes in the ability of adipocytes and acini isolated from lactating rats to synthesize lipids. The capacity to synthesize fatty acids and phospholipids decreased in the mammary gland and increased in adipocytes by bromocryptine treatment. In the mammary gland, the maximum potential activity of the pentose shunt as well as the specific activities of the pathway dehydrogenases were significantly reduced by bromocryptine treatment. Simultaneously, adipose tissue increased its lipogenic capacity but neither the maximum potential of the shunt nor the specific activities of the pentose phosphate shunt dehydrogenases were significantly changed with respect to the control lactating rats. Thus, a differential regulatory mechanism(s) of the pentose phosphate shunt activity appears to operate in these two tissues. Adipocytes from lactating rats showed a poor responsiveness to insulin in terms of lipid synthesis from glucose. In contrast, in adipocytes from bromocryptine treated rats insulin was able to increase lipid synthesis (105%). Sheep prolactin administration in vivo partially reversed the effects of bromocryptine. These data suggest that prolactin mediates adipocytes resistance to insulin during lactation. Phospholipid synthesis, as occurred in fatty acid synthesis, is increased in adipose tissue and decreased in mammary gland by bromocryptine treatment. However, -adrenergic stimulation increases phosphatidylinositol turnover to about the same percentages in both mammary gland acini and adipocytes from lactating rats independently of bromocryptine treatment.     

Injury-induced insulin resistance in adipose tissue

Hyperglycemia and insulin resistance are common findings in critical illness. Patients in the surgical ICU are frequently treated for this 'critical illness diabetes' with intensive insulin therapy, resulting in a substantial reduction in morbidity and mortality. Adipose tissue is an important insulin target tissue, but it is not known whether adipose tissue is affected by critical illness diabetes. In the present study, a rodent model of critical illness diabetes was used to determine whether adipose tissue becomes acutely insulin resistant and how insulin signaling pathways are being affected. There was a reduction in insulin-induced phosphorylation of IR, IRS-1, Akt and GSK-3β. Since insulin resistance occurs rapidly in adipose tissue, but before the insulin resistance in skeletal muscle, it may play a role in the initial development of critical illness diabetes.     

Different metabolic responses of human brown adipose tissue to activation by cold and insulin

We investigated the metabolism of human brown adipose tissue (BAT) in healthy subjects by determining its cold-induced and insulin-stimulated glucose uptake and blood flow (perfusion) using positron emission tomography (PET) combined with computed tomography (CT). Second, we assessed gene expression in human BAT and white adipose tissue (WAT). Glucose uptake was induced 12-fold in BAT by cold, accompanied by doubling of perfusion. We found a positive association between whole-body energy expenditure and BAT perfusion. Insulin enhanced glucose uptake 5-fold in BAT independently of its perfusion, while the effect on WAT was weaker. The gene expression level of insulin-sensitive glucose transporter GLUT4 was also higher in BAT as compared to WAT. In conclusion, BAT appears to be differently activated by insulin and cold; in response to insulin, BAT displays high glucose uptake without increased perfusion, but when activated by cold, it dissipates energy in a perfusion-dependent manner.     

Growth hormone inhibition of glucagon- and cAMP-induced lipolysis by chicken adipose tissue in vitro

The ability of growth hormone (GH) to inhibit the early (first hour) lipolytic response to glucagon and cAMP was investigated using chicken adipose tissue explants in vitro. In the first hour of incubation, GH inhibited glucagon, 8-bromo-3',5'-cyclic adenosine monophosphate (8-bromo-cAMP), and 1-isobutyl-3-methyl-xanthine (IBMX) induced glycerol release. The antilipolytic effect of GH was dose dependent, with inhibition of glucagon and 8-bromo-cAMP observed in the presence of as little as 100 ng/ml GH. In the fourth hour of incubation (late lipolytic response), GH (10, 100, or 1000 ng/ml) enhanced the lipolytic action of glucagon.     

Enzyme and protein turnover in adipose tissue in pregnancy and lactation

1. The relative rates of synthesis of fatty acid synthetase and the pyruvate dehydrogenase complex were measured in adipose tissue in virgin, late pregnant and early lactating rats after injection of l-[2,3-³H]alanine. The relative rate of synthesis of fatty acid synthetase decreased approximately 4-fold between 2 days prepartum and 2 days postpartum. The relative rate of synthesis of the pyruvate dehydrogenase complex did not change. 2. The fractional rate of total adipose tissue protein synthesis was measured by constant infusion with l-[U-¹⁴C]tyrosine. Total protein synthesis did not differ in virgin and 2-day lactating rats. The half-life of adipose tissue protein in virginn rats determined by decay of ¹⁴C label from protein after injection of NaH¹⁴CO₃ was 86.9 ± 6.7 h. This is in close agreement witht the half-life (82.5 ± 20 h) calculated from the fractional rate of protein synthesis determined by the constant infusion method.