Changes in lipogenesis and lipolysis associated with recovery from reversible obesity in mature female rats

Reversible obesity provides a model for demonstration of weight regulation in mature animals. Changes in body composition and in vitro adipose and hepatic lipid synthesis and adipose lipolysis of rats recovering from enforced weight gain were examined to determine whether correction of weight was facilitated by metabolic changes independent of those resulting from hypophagia and negative energy balance. Female Sprague-Dawley rats (200 g) were divided into three groups. Controls ate ad libitum, tube-fed control rats were weight matched to controls. Two-hundred percent-fed rats were tube-fed twice control intake. After 26 days tube feeding stopped and a subgroup from each treatment was killed for determination of body composition and in vitro tissue metabolism. Further subgroups were examined 5, 10, 15, and 36 days later. At the end of overfeeding 200%-fed rats were hypophagic and had high rates of adipose and hepatic lipid synthesis, which soon returned to normal. Gross changes in body fat mass were corrected by hypophagia and increased adipose lipolysis. The remaining small excess in body fat appeared to be corrected by decreased basal and insulin-stimulated adipose fatty acid synthesis when food intake had returned to normal.     

Fatty acid cycling in the fasting rat

Adipose tissue lipolysis and fatty acid reesterification by liver and adipose tissue were investigated in rats fasted for 15 h under basal and calorigenic conditions. The fatty acid flux initiated by adipose fat lipolysis in the fasted rat is mostly futile and is characterized by reesterification of 57% of lipolyzed free fatty acid (FFA) back into adipose triglycerides (TG). About two-thirds of FFA reesterification are carried out before FFA release into plasma, whereas the rest consists of plasma FFA extracted by adipose tissue. Thirty-six percent of the fasting lipolytic flux is accounted for by oxidation of plasma FFA, whereas only a minor fraction is channeled into hepatic very low density lipoprotein-triglycerides (VLDL-TG). Total body calorigenesis induced by thyroid hormone treatment and liver-specific calorigenesis induced by treatment with beta, beta'-tetramethylhexadecanedioic acid (Medica 16) are characterized by a 1.7- and 1.3-fold increase in FFA oxidation, respectively, maintained by a 1.5-fold increase in adipose fat lipolysis. Hepatic reesterification of plasma FFA into VLDL-TG is negligible under both calorigenic conditions. Hence, total body fatty acid metabolism is regulated by adipose tissue as both source and sink. The futile nature of fatty acid cycling allows for its fine tuning in response to metabolic demands.     

Regional uptake of meal fatty acids in humans

Two protocols were performed to study meal fatty acid metabolism. In protocol 1, 14 patients scheduled for elective intra-abdominal surgery (11 undergoing bariatric surgery for severe obesity) consumed a meal containing [3H]triolein in the evening before surgery. This allowed us to measure adipose tissue lipid specific activity (SA) in mesenteric and omental, deep and superficial abdominal subcutaneous adipose tissue. Intra-abdominal adipose tissue lipid SA was greater than subcutaneous lipid SA. There were no significant differences between mesenteric and omental or between deep and superficial abdominal subcutaneous adipose tissue. In protocol 2, meal fatty acid oxidation and uptake into subcutaneous and omental adipose tissue ([3H]triolein) were measured in six normal, healthy volunteers. Meal fatty acid oxidation (3H2O generation) plus that remaining in plasma ( approximately 1%) plus uptake into upper body subcutaneous, lower body subcutaneous, and visceral fat allowed us to account for 98 +/- 6% of meal fatty acids 24 h after meal ingestion. We conclude that omental fat is a good surrogate for visceral fat and that abdominal subcutaneous fat depots are comparable with regard to meal fatty acid metabolic studies. Using [3H]triolein, we were able to account for virtually 100% of meal fatty acids 24 h after meal ingestion. These results support the meal fatty acid tracer model as a way to study the metabolic fate of dietary fat.     

DNA microarrays to define and search for genes associated with obesity

One of the major goals of this review was to identify obesity-specific gene profiles in animal models to help comprehend the pathogenic mechanisms and the prediction of the phenotypic outcomes of obesity and its associated metabolic diseases. The genomic examination of insulin-sensitive tissues, such as the adipose and hepatic tissues, has provided a wealth of information about the changes in gene expression in obesity and its associated metabolic diseases. The overexpression of genes related to inflammation, immune response, adhesion molecules, and lipid metabolism is a major characteristic of white adipose tissue, while the overexpression of the genes related to lipid metabolism, adipocyte differentiation, defense, and stress responses is noticeable in the non-alcoholic fatty liver of obese rodents. The hepatic-gene expression profiles led us to hypothesize that in obese rodents, the livers are supplied with large amounts of free fatty acids under conditions associated with obesity either through increased fatty acid biosynthesis or through decreased fatty acid oxidation, which may lead to increased mitochondrial respiratory activity. The wide list of genes that were identified in previous studies could be a source of potential therapeutic targets because most of these genes are involved in the key mechanisms of obesity development, from adipocyte differentiation to the disturbance of metabolism.     

Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function

Fatty acids derived from adipose tissue lipolysis, intramyocellular triacylglycerol lipolysis, or de novo lipogenesis serve a variety of functions in skeletal muscle. The two major fates of fatty acids are mitochondrial oxidation to provide energy for the myocyte and storage within a variety of lipids, where they are stored primarily in discrete lipid droplets or serve as important structural components of membranes. In this review, we provide a brief overview of skeletal muscle fatty acid metabolism and highlight recent notable advances in the field. We then 1) discuss how lipids are stored in and mobilized from various subcellular locations to provide adaptive or maladaptive signals in the myocyte and 2) outline how lipid metabolites or metabolic byproducts derived from the actions of triacylglycerol metabolism or β-oxidation act as positive and negative regulators of insulin action. We have placed an emphasis on recent developments in the lipid biology field with respect to understanding skeletal muscle physiology and discuss unanswered questions and technical limitations for assessing lipid signaling in skeletal muscle.     

The role of dietary fatty acids in the pathology of metabolic syndrome

Dysfunctional lipid metabolism is a key component in the development of metabolic syndrome, a very frequent condition characterized by dyslipidemia, insulin resistance, abdominal obesity and hypertension, which are related to an elevated risk for type 2 diabetes mellitus. The prevalence of metabolic syndrome is strongly associated with the severity of obesity; its physiopathology is related to both genetics and food intake habits, especially the consumption of a high-caloric, high-fat and high-carbohydrate diet. With the progress of scientific knowledge in the field of nutrigenomics, it was possible to elucidate how the majority of dietary fatty acids influence plasma lipid metabolism and also the genes expression involved in lipolysis and lipogenesis within hepatocytes and adipocytes. The aim of this review is to examine the relevant mechanistic aspects of dietary fatty acids related to blood lipids, adipose tissue metabolism, hepatic fat storage and inflammatory process, all of them closely related to the genesis of metabolic syndrome.     

Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity

Adipose tissue lipolysis provides circulating FFAs to meet the body's lipid fuel demands. FFA release is well regulated in normal-weight individuals; however, in upper-body obesity, excess lipolysis is commonly seen. This abnormality is considered a cause for at least some of the metabolic defects (dyslipidemia, insulin resistance) associated with upper-body obesity. "Normal" lipolysis is sex-specific and largely determined by the individual's resting metabolic rate. Women have greater FFA release rates than men without higher FFA concentrations or greater fatty acid oxidation, indicating that they have greater nonoxidative FFA disposal, although the processes and tissues involved in this phenomenon are unknown. Therefore, women have the advantage of having greater FFA availability without exposing their tissues to higher and potentially harmful FFA concentrations. Upper-body fat is more lipolytically active than lower-body fat in both women and men. FFA released by the visceral fat depot contributes only a small percentage of systemic FFA delivery. Upper-body subcutaneous fat is the dominant contributor to circulating FFAs and the source of the excess FFA release in upper-body obesity. We believe that abnormalities in subcutaneous lipolysis could be more important than those in visceral lipolysis as a cause of peripheral insulin resistance. Understanding the regulation of FFA availability will help to discover new approaches to treat FFA-induced abnormalities in obesity.     

Lipid metabolism in mammalian tissues and its control by retinoic acid

Evidence has accumulated that specific retinoids impact on developmental and biochemical processes influencing mammalian adiposity including adipogenesis, lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with retinoic acid, in particular, has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents by enhancing fat mobilization and energy utilization systemically, in tissues including brown and white adipose tissues, skeletal muscle and the liver. Nevertheless, controversial data have been reported, particularly regarding retinoids' effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported activities of retinoids on different aspects of lipid metabolism in key tissues, focusing on retinoic acid. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.     

Glucose and fatty acid metabolism in McA-RH7777 hepatoma cells vs. rat primary hepatocytes: responsiveness to nutrient availability

The overabundance of dietary fats and simple carbohydrates contributes significantly to obesity and metabolic disorders associated with obesity. The liver balances glucose and lipid distribution, and disruption of this balance plays a key role in these metabolic syndromes. We investigated (1) how hepatocytes balance glucose and fatty acid metabolism when one or both nutrients are supplied in abundance and (2) whether rat hepatoma cells (McA-RH7777) reflect nutrient partitioning in a similar manner as compared with primary hepatocytes. Increasing media palmitate concentration increased fatty acid uptake, triglyceride synthesis and beta-oxidation. However, hepatoma cells had a 2-fold higher fatty acid uptake and a 2-fold lower fatty acid oxidation as compared with primary hepatocytes. McA-RH7777 cells did not synthesize significant amounts of glycogen and preferentially metabolized the glucose into lipids or into oxidation. In primary hepatocytes, the glucose was mostly spared from oxidation and instead partitioned into both de novo glycogen and lipid synthesis. Overall, lipid production was rapidly induced in response to either glucose or fatty acid excess and this may be one of the earliest indicators of metabolic syndrome development associated with nutrient excess.     

Prolactin activation of the long form of its cognate receptor causes increased visceral fat and obesity in males as shown in transgenic mice expressing only this receptor subtype

To date the best defined function of prolactin (PRL) is its action on the ovary and mammary gland, although it has also been shown to have an effect on lipid metabolism. Using mice engineered to express only the long form of the prolactin receptor (PRL-RL), we demonstrate that PRL acting through PRL-RL alone causes severe adipose accumulation in visceral fat of males at 6 months of age. The increase in visceral fat accumulation is attributed to loss of adipose-derived leptin, which results in diminished lipolysis. The reduction in leptin also corresponds to decreased activation of AMP-activated protein kinase (AMPK), which further results in diminished fatty acid oxidation and increased fatty acid synthesis. Interestingly, the blunted AMPK response was only observed in adipose tissue and not in liver suggesting that this PRL mediated effect is tissue specific. A glucose tolerance study inferred that PRL-RL mice may suffer from insulin resistance or a reduction in insulin production that is not due to aberrant expression of glucose transporter 4 (Glut4). Collectively, our findings demonstrate that PRL signaling through the long form receptor causes reduced fatty acid oxidation, increased lipid storage, glucose intolerance, and obesity. These findings are of great importance towards understanding the etiology of obesity associated with hyperprolactinemia in humans as well as the role of PRL as a metabolic regulator in adipose tissue.     

Panax red ginseng extract regulates energy expenditures by modulating PKA dependent lipid mobilization in adipose tissue

Regulation of balance between lipid accumulation and energy consumption is a critical step for the maintenance of energy homeostasis. Here, we show that Panax red ginseng extract treatments increased energy expenditures and prevented mice from diet induced obesity. Panax red ginseng extracts strongly activated Hormone Specific Lipase (HSL) via Protein Kinase A (PKA). Since activation of HSL induces lipolysis in WAT and fatty acid oxidation in brown adipose tissue (BAT), these results suggest that Panax red ginseng extracts reduce HFD induced obesity by regulating lipid mobilization.     

Adipose tissue fatty acid metabolism and cardiovascular disease

PURPOSE OF REVIEW: Fatty acid and triacylglycerol metabolism in adipose tissue may be involved in the generation of risk factors for cardiovascular disease and type 2 diabetes. Pharmaceutical companies are targeting adipocyte metabolism in their search for drugs for treating, or reducing the risk of, these conditions. We review new developments in adipose tissue fatty acid metabolism and how that might relate to cardiovascular disease. RECENT FINDINGS: Fatty acid release from human adipose tissue is oscillatory, with a period of about 12 min. Remarkably, oscillatory fatty acid release is also seen in isolated adipocytes. Further evidence has emerged that not all adipose depots are equal, and that lower-body adipose tissue may exert protective effects against cardiovascular disease. There have been a number of developments in the area of fatty acid handling by adipocytes. Fatty acid binding proteins are clearly important in regulating fatty acid metabolism, with striking protection against atherosclerosis in mice deficient in both the binding proteins expressed in adipocytes. The demonstration that adipocytes lacking hormone-sensitive lipase still display lipolysis has led to the identification of novel lipases that may play crucial roles in adipose tissue fatty acid metabolism. Further evidence has accrued of the interaction between hormone-sensitive lipase and perilipin, the protein that coats the adipocyte lipid droplet. SUMMARY: Recent developments in our understanding of adipose tissue fatty acid metabolism open up the possibility of new pharmaceutical targets. However, interference with adipose tissue fatty acid metabolism is not to be undertaken lightly and needs a clear understanding of the normal role of adipocyte lipolysis.     

Effects of acute administration of doxazosin on fasting and postprandial haemodynamics and lipid metabolism in healthy subjects.

The selective alpha1 -adrenoceptor antagonist doxazosin has apparently beneficial effects on insulin sensitivity and on plasma lipid concentrations. In order to understand these effects better, we investigated the acute effects of doxazosin on adipose tissue and forearm blood flow and on postprandial lipid metabolism in healthy subjects. Nine subjects were studied in a balanced, placebo-controlled design. Pulse rate, blood pressure, forearm and subcutaneous adipose tissue blood flow were measured before and for 6 h after a mixed meal, with concomitant measurements of blood metabolites and insulin. Doxazosin increased pulse rate (p = 0.02) and forearm blood flow (p < 0.01 in fasting state), and decreased vascular resistance in forearm (p < 0.05 for fasting values) and subcutaneous abdominal adipose tissue (p = 0.04). Fasting plasma non-esterified fatty acid concentrations were increased by 40 % (p < 0.05). No other metabolic effects were detected. The effects on adipose tissue vascular resistance and lipolysis (reflected in elevated non-esterified fatty acid concentrations) were unexpected, as these are usually considered to be mediated by the balance of alpha2 - and beta-adrenoceptor activity in humans. We conclude that alpha1 -adrenoceptor activity may be more important in regulation of human lipid metabolism than previously recognized.     

Molecular evolution of Cide family proteins: Novel domain formation in early vertebrates and the subsequent divergence

Background  

Cide family proteins including Cidea, Cideb and Cidec/Fsp27, contain an N-terminal CIDE-N domain that shares sequence similarity to the N-terminal CAD domain (NCD) of DNA fragmentation factors Dffa/Dff45/ICAD and Dffb/Dff40/CAD, and a unique C-terminal CIDE-C domain. We have previously shown that Cide proteins are newly emerged regulators closely associated with the development of metabolic diseases such as obesity, diabetes and liver steatosis. They modulate many metabolic processes such as lipolysis, thermogenesis and TAG storage in brown adipose tissue (BAT) and white adipose tissue (WAT), as well as fatty acid oxidation and lipogenesis in the liver.     

Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans

Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150?mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30?days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30?days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.     

Regulation of lipid flux between liver and adipose tissue during transient hepatic steatosis in carnitine-depleted rats

Rats with carnitine deficiency due to trimethylhydrazinium propionate (mildronate) administered at 80 mg/100 g body weight per day for 10 days developed liver steatosis only upon fasting. This study aimed to determine whether the transient steatosis resulted from triglyceride accumulation due to the amount of fatty acids preserved through impaired fatty acid oxidation and/or from up-regulation of lipid exchange between liver and adipose tissue. In liver, mildronate decreased the carnitine content by approximately 13-fold and, in fasted rats, lowered the palmitate oxidation rate by 50% in the perfused organ, increased 9-fold the triglyceride content, and doubled the hepatic very low density lipoprotein secretion rate. Concomitantly, triglyceridemia was 13-fold greater than in controls. Hepatic carnitine palmitoyltransferase I activity and palmitate oxidation capacities measured in vitro were increased after treatment. Gene expression of hepatic proteins involved in fatty acid oxidation, triglyceride formation, and lipid uptake were all increased and were associated with increased hepatic free fatty acid content in treated rats. In periepididymal adipose tissue, mildronate markedly increased lipoprotein lipase and hormone-sensitive lipase activities in fed and fasted rats, respectively. On refeeding, carnitine-depleted rats exhibited a rapid decrease in blood triglycerides and free fatty acids, then after approximately 2 h, a marked drop of liver triglycerides and a progressive decrease in liver free fatty acids. Data show that up-regulation of liver activities, peripheral lipolysis, and lipoprotein lipase activity were likely essential factors for excess fat deposit and release alternately occurring in liver and adipose tissue of carnitine-depleted rats during the fed/fasted transition.