Metabolic Response Of Liver Research Articles

238-LB: Erythropoietin Receptor–Mediated Erythropoietin Regulation of Energy Metabolism in Mice

EPO receptor (EPOR) expression in white adipose tissue (WAT) mediates EPO metabolic activity and mitochondrial biogenesis. Mice that lack EPOR in adipose tissue have increase fat mass accumulation, increased susceptibility to diet induced obesity and decreased WAT mitochondrial activity. Here we assess the potential for EPO to promote a metabolic response in liver, brown adipose tissue and skeletal muscle by assessing the extent of EPOR expression using the EpoR-dtTomato-Cre mouse. We quantified EPOR in liver, brown adipose tissue and soleus muscle compared with EPOR expression in subcutaneous and epididymal WAT and found the highest level in WAT by mRNA, protein and immunohistochemical analyses. Elevated EPO by intraperitoneal injection or by transgene over expression resulted in tissue specific changes in gene expression. In liver, EPO decreased expression of genes involved in gluconeogenesis and triglyceride secretion. In brown adipose tissue, EPO increased expression of thermogenic genes. In subcutaneous WAT, EPO decreased genes involved in lipogenesis. In soleus muscle, EPO decreased expression of lipolytic genes. These findings indicate that increased EPO decreases lipogenesis gene LPI, ACC1, ACC2 and Fas expression in the BAT, skeletal muscle, ScWAT, liver and eWAT and increases lipolysis gene Atgl and Hsl expression in the BAT, ScWAT, skeletal muscle, and Atgl expression in the liver and eWAT. Measurements of energy metabolism did not detect any changes associated with EPO treatment in energy expenditure, respiratory exchange ratio, locomotor activity and total activity. However, as observed in WAT, we also find that EPO promotes mitochondria activity in liver, brown adipose tissue and skeletal muscle indicated by elevated gene expression of CytC, Idh3α, Cpt1, Pgc-1α and Cox7a1. Together, these data support the hypothesis that EPO promotes lipolysis and inhibits fat synthesis to regulate body weight and fat mass. In addition, EPO may regulate glucose metabolism via inhibition of gluconeogenesis. Disclosure W. Yin: None. H. Rogers: None. P. K. Rajvanshi: None. X. An: None. M. Gassmann: None.

Oil from transgenic Camelina sativa as a source of EPA and DHA in feed for European sea bass (Dicentrarchus labrax L.)

Aquaculture, the fastest growing food production sector cannot continue to rely on finite stocks of marine fish as the primary source of the omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFA), eicosapentaenoic acid (EPA; 20:5n3) and docosahexaenoic acid (DHA; 22:6n-3), for feeds. A four-month feeding trial was conducted to investigate the impact of a de novo oil, with high levels of EPA and DHA, obtained from transgenic Camelina sativa on growth performance, tissue fatty acid profiles, and expression of lipid metabolism genes when used as a replacement for fish oil in feed for European seabass (Dicentrachus labrax). Triplicate groups of 50 juvenile fish (initial weight 16.7 ± 0.92 g) per tank were fed for 4 months with one of three isolipidic and isoproteic experimental diets consisting of a standard diet containing a commercial blend of fish oil and rapeseed oil (CFO), a diet containing transgenic Camelina oil (TCO), or a blend of fish oil and rapeseed oil with enhanced levels of EPA and DHA (EFO) formulated to match the n-3 LC-PUFA profile of the TCO feed. Final weight of fish fed the GM-derived oil was not different to fish fed either CFO or EFO. Slight lower growth performance of fish fed TCO at the beginning of the trial was related to transient reduced feed intake, possibly caused by glucosinolates in the raw Camelina sativa oil. The GM-derived oil improved the nutritional quality of the fish fillet by enhancing total n-3 PUFA levels compared to the fish fed the other two feeds, and maintained flesh EPA and DHA at the same levels as in fish fed the diets containing fish oil. The metabolic response in liver and intestine was generally relatively mild although diets TCO and EFO seemed to trigger a metabolic response consisting of an up-regulation of both β-oxidation (cpt1a) and fatty acid transport (fabp1), possibly reflecting higher levels of LC-PUFA. Overall, the present study indicated that an oil of terrestrial origin, Camelina sativa, when engineered to contain high levels of EPA and DHA can replace fish oil in feeds for European seabass with no detrimental impact on growth or feed efficiency, while also maintaining or increasing tissue n-3 LC-PUFA contents.

Metabolic response in liver and Brockmann bodies of rainbow trout to inhibition of lipolysis; possible involvement of the hypothalamus-pituitary-interrenal (HPI) axis.

We previously demonstrated in rainbow trout that the decrease in circulating levels of fatty acid (FA) induced by treating fish with SDZ WAG 994 (SDZ) induced a counter-regulatory response in which the activation of the hypothalamus-pituitary-interrenal (HPI, equivalent to mammalian hypothalamus-pituitary-adrenal) axis was likely involved. This activation, probably not related to the control of food intake through FA sensor systems but to the modulation of lipolysis in peripheral tissues, liver and Brockmann bodies (BB, the main site of pancreatic endocrine cells in fish), would target the restoration of FA levels in plasma. To assess this hypothesis, we lowered circulating FA levels by treating fish with SDZ alone, or SDZ in the presence of metyrapone (an inhibitor of cortisol synthesis). In liver, the changes observed were not compatible with a direct FA-sensing response but with a stress response, which allows us to suggest that the detection of a FA decrease in the hypothalamus elicits a counter-regulatory response in liver, resulting in an activation of lipolysis to restore FA levels in plasma. The activation of these metabolic changes in liver could be attributable to the activation of the HPI axis and/or to the action of sympathetic pathways. In contrast, in BB, changes in circulating FA levels induce changes in several parameters compatible with the function of FA-sensing systems informing about the decrease in circulating FA levels.

Sequential Use of 90Y Microspheres Radioembolization and 177Lu-Dotatate in Pluri-Metastatic Neuroendocrine Tumors: A Case Report

(90)Y radioembolization and peptide-receptor radionuclide therapy (PRRT) with(177)Lu-DOTATATE are both effective treatments for patients with inoperable neuroendocrine metastatic tumors (NET). We report the case of a 72-year-old man with severe functional syndrome due to a metastatic NET. (68)Ga-DOTATOC positron-emission tomography (PET) revealed high somatostatin receptor expression in a gross liver metastasis, in one abdominal lymph node and in several skeletal lesions. The patient underwent liver radioembolization with (90)Y-resin microspheres followed by fourcycles of PRRT with(177)Lu-DOTATATE. After 3months, a complete remission of the functional syndrome was observed. (68)Ga-DOTATOC PET demonstrated a complete response for skeletal and lymph nodal lesions with a residual bulky mass in the liver. Therefore a further (90)Y radioembolization was performed as consolidation treatment for the hepatic lesion. Six months after these combined treatments, (68)Ga-DOTATOC PET demonstrated complete metabolic response in liver and stable extrahepatic lesions. No significant long-term adverse reactions were registered. To our knowledge, the sequential use of (90)Y radiembolization before and after PRRT in a liver-dominant advanced NET has not been reported in the literature and this case suggests that these combined treatments can be safe and effective.

Dimer interface rearrangement of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase rat liver isoenzyme by cAMP-dependent Ser-32 phosphorylation

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) is a key regulator of carbohydrate metabolism in liver. The goal of this study was to elucidate the regulatory role of Ser-32 phosphorylation on the kinase domain mediated dimerization of PFK-2/FBPase-2. Fluorescence-based mammalian two-hybrid and sensitized emission fluorescence resonance energy transfer analyses in cells revealed preferential binding within homodimers in contrast to heterodimers. Using isolated proteins a close proximity of two PFK-2/FBPase-2 monomers was only detectable in the phosphorylated enzyme dimer. Thus, a flexible kinase interaction mode exists, suggesting dimer conformation mediated coupling of hormonal and posttranslational enzyme regulation to the metabolic response in liver. Structured summary of protein interactionsPFK-2/FBPase-2 physically interacts with PFK-2/FBPase-2 by fluorescent resonance energy transfer (View Interaction: 1, 2)PFK-2/FBPase-2 physically interacts with PFK-2/FBPase-2 by two hybrid (View interaction)

Synthesis of acute-phase proteins in perfused liver following administration of recombinant interleukin 1α to normal or adrenalectomized rats

The purpose of this study was to investigate the effects of recombinant interleukin lα (rIL-1α) on metabolic rate and synthesis of acute-phase proteins in intact and adrenalectomized rats. Animals were housed in metabolic cages with daily recording of food intake and body weight. Twice daily, for 3 days, the rats were injected intraperitoneally with 5000 LAF U of human rIL-1α, purified from Escherichia coli. Control animals were pair-fed and received corresponding injections with saline. In the morning of the fourth day, resting energy expenditure (REE) was determined by indirect calorimetry, and synthesis of total secreted proteins, albumin, complement component C3, and seromucoid fraction was measured by radioimmunological method using rat-specific antisera and [ 3H]leucine in livers perfused for 2 hr. Food intake decreased by approximately 30% during rIL-1α administration to intact rats. The decrease in food intake occurred later and was less pronounced in adrenalectomized rats receiving rIL-1α. Growth rate was significantly reduced on the first day of rIL-1α treatment in intact rats, while there was no effect on growth rate in adrenalectomized animals. After rIL-1α administration, REE was increased by 26% in intact rats ( P < 0.001) and by 14% in adrenalectomized rats (N.S.). Increased synthesis rates of total secreted proteins, complement component C3, and seromucoid fraction were observed in livers of intact rats following rIL-1α administration. In adrenalectomized rats, only production of C3 was significantly increased after treatment with rIL-1α. Albumin synthesis rate was not changed in either group following rIL-1α injections. When heat-inactivated (100°C for 60 min) rIL-1α was administered, no changes in hepatic protein synthesis were observed, indicating that the small amounts of endotoxin present in the IL-1 solution did not account for the metabolic response in liver. The results suggest that IL-1α is at least a partial mediator of the acute-phase response in sepsis and that adrenal hormones may influence this response.

Lack of vasopressin receptors in liver, but not in kidney, of ob/ob mice.

The activity of phosphorylase a was measured in isolated hepatocytes from fed lean and ob/ob mice after addition of vasopressin, angiotensin, phenylephrine and glucagon. The binding of these hormones to purified liver plasma membranes was also determined. In hepatocytes of ob/ob mice, no increase in phosphorylase a was measured after addition of vasopressin, whereas the other hormones promoted an increase in the activity of the enzyme. No specific vasopressin receptors could be measured on purified liver plasma membrane of ob/ob mice. A decrease in the number of receptors for angiotensin and glucagon, without modification of the affinity, was also observed. No restoration of the number of vasopressin receptors was observed in liver of ob/ob mice starved for 3 days or in younger (5-6 weeks) animals. Vasopressin receptors and vasopressin-stimulated adenylate cyclase, measured on purified kidney medulla membranes, were similar in both lean and ob/ob mice. The data indicate a selective lack of vasopressin receptors and metabolic response in liver of the ob/ob mouse.

Effect of 1,3-diaminopropan-2-o1, an inhibitor of ornithine decarboxylase, on the metabolic response of liver to insulin.

The effect of diaminopropanol, an inhibitor of polyamine synthesis, on the metabolic response of liver to insulin was studied in streptozotocin-diabetic rats. Insulin elicited a prompt and very marked increase in ornithine and S-adenosylmethionine decarboxylase activities and in putrescine concentration. Pretreatment of rats with diaminopropanol prevented the increase in the decarboxylases and resulted in decreased spermidine and spermine content of liver. The insulin-induced increase in glycogen content was depressed by 50% and the increase in the rate of lipogenesis in vivo was completely prevented by prior injection of diaminopropanol. These studies implicate altered polyamine metabolism in the metabolic response of liver of streptozotocin-diabetic rats to insulin.