Impact of variation in the FTO gene on whole body fat distribution, ectopic fat, and weight loss

Polymorphisms in the fat mass- and obesity-associated (FTO) gene have been identified to be associated with obesity and diabetes in large genome-wide association studies. We hypothesized that variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single-nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 subjects. Two-hundred and four subjects participated in a lifestyle intervention program and were examined after a follow-up of 9 months. In the cross-sectional analysis, the A allele of rs8050136 in FTO was associated with a higher BMI, body fat, and lean body mass (all P < 0.001). There was a significant effect of variation in the FTO gene on subcutaneous fat (P < or = 0.05) and a trend for liver fat content, nonvisceral adipose tissue, and visceral fat (all P < or = 0.1). However, the single-nucleotide polymorphism was not associated with insulin sensitivity or secretion independent of BMI (all P > 0.05). During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. In conclusion, despite an association with BMI and whole body fat distribution, variation in the FTO locus has no effect on the success of a lifestyle intervention program.     

Relationship between the tissue level of cyclic AMP and the fat cell size of human adipose tissue.

The relationship between mean fat cell size, maximal tissue cyclic AMP concentration, and glycerol release was investigated in human subcutaneous adipose tissue incubated in vitro with or without isoprenaline or noradrenaline added at maximal effective concentrations. Basal and stimulated glycerol release and cyclic AMP concentration were each related to the fat cell size. Whether or not the phosphodiesterase inhibitor theophylline was present in the incubation system, basal and noradrenaline-induced cyclic AMP levels were significantly correlated with the fat cell size. The noradrenaline-induced cyclic AMP levels resulted in twice as rapid glycerol release as could be expected from the basal ratio between glycerol release and cyclic AMP. Furthermore, both basal and noradrenaline-induced glycerol release in relation to the cyclic AMP levels were more rapid in enlarge fat cells. It is concluded that basal and catecholamine-induced production of cyclic AMP is related to the fat cell size and that a quantitative relationship exists between rate of lipolysis and maximal tissue levels of cyclic AMP in human adipose tissue. Basal and noradrenaline-induced lipolysis are probably regulated by different mechanisms and the lipolytic sensitivity to cyclic AMP seems increased in large fat cells.     

Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels

The availability of mice containing an adipocyte lipid-binding protein (ALBP/aP2) gene disruption allowed for a direct examination of the presumed role of lipid-binding proteins in the mobilization and trafficking of intracellular fatty acids. Total body and epididymal fat pad weights, as well as adipose cell morphology, were unaltered in male ALBP/aP2 disrupted mice when compared to their wild-type littermates. Analysis of adipocytes isolated from wild-type and ALBP/aP2 null mice revealed that a selective 40- and 13-fold increase in the level of the keratinocyte lipid-binding protein (KLBP) mRNA and protein, respectively, accompanied the ALBP/aP2 gene disruption. Although KLBP protein was significantly up-regulated, the total lipid-binding protein level decreased 8 -fold as a consequence of the disruption. There was no appreciable difference in the rate of fatty acid influx or esterification in adipocytes of wild-type and ALBP/aP2 null animals. To the contrary, basal lipolysis decreased approximately 40% in ALBP/aP2 nulls as compared to wild-type littermates. The glycerol release from isproterenol-stimulated ALBP/aP2 null fat cells was similarly reduced by approximately 35%. Consistent with a decrease in basal efflux, the non-esterified fatty acid (NEFA) level was nearly 3-fold greater in adipocytes from ALBP/aP2 nulls as compared to wild-type animals. The significant decrease in both basal and isoproterenol-stimulated lipolysis in adipose tissue of ALBP/aP2 null mice supports the model whereby intracellular lipid-binding proteins function as lipid chaperones, facilitating the movement of fatty acids out of the fat cell.     

Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes

High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 μg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold (P < 0.01 vs basal), respectively. From 100 ng/ml to 1 μg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level (P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.     

The role of neutral lipases in human adipose tissue lipolysis

PURPOSE OF REVIEW: The aim of this article is to describe the relative roles of hormone sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis. RECENT FINDINGS: Until recently, only hormone sensitive lipase was considered important for the regulation of lipolysis within fat cells. Recent rodent studies have suggested that adipose triglyceride lipase may, however, be more important. The few human adipose triglyceride lipase studies that have been published point to species differences between humans and rodents. Selective inhibition of hormone sensitive lipase in human fat cells completely counteracts hormone-activated lipolysis, though there is a considerable (>50%) residual nonhormonal (basal) lipolysis. In rodents, adipose triglyceride lipase enzyme activity is stimulated by a cofactor termed CGI-58. In the absence of CGI-58, lipase activity in fat cells is much higher for hormone sensitive lipase than adipose triglyceride lipase. Hormone sensitive lipase expression is regulated by obesity and body weight reduction (decreased and increased, respectively), but this is not the case for adipose triglyceride lipase. A role of adipose triglyceride lipase in human lipolysis is suggested by studies of gene polymorphisms. SUMMARY: Two lipases the 'old' hormone sensitive lipase and the 'new' adipose triglyceride lipase are of importance for the regulation of lipolysis in rodent fat cells. In humans, adipose triglyceride lipase seems essential for maintaining basal lipolytic activity, while hormone sensitive lipase is the enzyme most responsive to stimulated lipolysis.     

The expression of FTO in human adipose tissue is influenced by fat depot,adiposity, and insulin sensitivity

Objective: The fat mass and obesity associated (FTO) gene is related to obesity, but the regulation of FTO expression in adipose tissue is not fully understood. We investigated FTO expression in paired subcutaneous and omental adipose tissues (SAT and OAT) from healthy women undergoing gynecological surgeries, and its relation with adiposity and insulin sensitivity. Design and Methods: FTO expression in SAT of type 2 diabetic patients treated or not with Rosiglitazone was also compared. Results: Both the mRNA and protein levels of FTO were higher in OAT from women than in SAT. Only OAT FTO protein levels negatively correlated with BMI and body fat mass, whereas SAT FTO mRNA levels were negatively correlated with subcutaneous fat deposition. In addition, SAT FTO mRNA and protein levels were increased in insulin resistant women (high HOMA) compared to insulin sensitive women (low HOMA), whereas OAT FTO expression was not different between these two subgroups. Interestingly, FTO mRNA levels were increased in SAT of type 2 diabetic patients, and treatment of diabetics with Rosiglitazone improved insulin sensitivity and reduced SAT FTO mRNA levels. Lastly, FTO expression was transiently increased in the early phase of 3T3‐L1 cell differentiation, which coincides with the induction of PPARγ2 expression. However, partial reduction of FTO did not impact PPARγ2 expression and adipocyte differentiation. Conclusion: Therefore, FTO gene expression is higher in OAT than in SAT in lean to moderately obese women. OAT FTO expression is associated with adiposity, whereas SAT FTO expression is associated with insulin sensitivity. These associations are independent of an effect of FTO on adipocyte differentiation.     

Adipogenic and lipolytic effects of chronic glucocorticoid exposure

Glucocorticoids have been proposed to be both adipogenic and lipolytic in action within adipose tissue, although it is unknown whether these actions can occur simultaneously. Here we investigate both the in vitro and in vivo effects of corticosterone (Cort) on adipose tissue metabolism. Cort increased 3T3-L1 preadipocyte differentiation in a concentration-dependent manner, but did not increase lipogenesis in adipocytes. Cort increased lipolysis within adipocytes in a concentration-dependent manner (maximum effect at 1-10 μM). Surprisingly, removal of Cort further increased lipolytic rates (～320% above control, P < 0.05), indicating a residual effect on basal lipolysis. mRNA and protein expression of adipose triglyceride lipase and phosphorylated status of hormone sensitive lipase (Ser563/Ser660) were increased with 48 h of Cort treatment. To test these responses in vivo, Sprague-Dawley rats were subcutaneously implanted with wax pellets with/without Cort (300 mg). After 10 days, adipose depots were removed and cultured ex vivo. Both free fatty acids and glycerol concentrations were elevated in fed and fasting conditions in Cort-treated rats. Despite increased lipolysis, Cort rats had more visceral adiposity than sham rats (10.2 vs. 6.9 g/kg body wt, P < 0.05). Visceral adipocytes from Cort rats were smaller and more numerous than those in sham rats, suggesting that adipogenesis occurred through preadipocyte differentiation rather than adipocyte hypertrophy. Visceral, but not subcutaneous, adipocyte cultures from Cort-treated rats displayed a 1.5-fold increase in basal lipolytic rates compared with sham rats (P < 0.05). Taken together, our findings demonstrate that chronic glucocorticoid exposure stimulates both lipolysis and adipogenesis in visceral adipose tissue but favors adipogenesis primarily through preadipocyte differentiation.     

Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects.

Decreased lipolytic effect of catecholamines in adipose tissue has repeatedly been demonstrated in obesity and may be a cause of excess accumulation of body fat. However, the mechanisms behind this lipolysis defect are unclear. The role of hormone-sensitive lipase was examined using abdominal subcutaneous adipocytes from 34 obese drug-free and otherwise healthy males or females and 14 non-obese control subjects. The enzyme catalyzes the rate-limiting step of the lipolysis pathway. The maximum lipolytic capacity of fat cells was significantly decreased in obesity when measured using either a non-selective beta-adrenergic receptor agonist (isoprenaline) or a phosphodiesterase resistant cyclic AMP analogue (dibutyryl cyclic AMP). Likewise, enzyme activity, protein expression, and mRNA of hormone-sensitive lipase were significantly decreased in adipocytes of obese subjects. The findings were not influenced by age or gender. The data suggest that a decreased expression of hormone-sensitive lipase in subcutaneous fat cells, which in turn causes decreased enzyme function and impaired lipolytic capacity of adipocytes, is present in obesity. Impaired expression of the hormone-sensitive lipase gene might at least in part explain the enzyme defect.     

Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis

Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) regulate adipocyte lipolysis in rodents. The purpose of this study was to compare the roles of these lipases for lipolysis in human adipocytes. Subcutaneous adipose tissue was investigated. HSL and ATGL protein expression were related to lipolysis in isolated mature fat cells. ATGL or HSL were knocked down by RNA interference (RNAi) or selectively inhibited, and effects on lipolysis were studied in differentiated preadipocytes or adipocytes derived from human mesenchymal stem cells (hMSC). Subjects were all women. There were 12 lean controls, 8 lean with polycystic ovary syndrome (PCOS), and 27 otherwise healthy obese subjects. We found that norepinephrine-induced lipolysis was positively correlated with HSL protein levels (P < 0.0001) but not with ATGL protein. Women with PCOS or obesity had significantly decreased norepinephrine-induced lipolysis and HSL protein expression but no change in ATGL protein expression. HSL knock down by RNAi reduced basal and catecholamine-induced lipolysis. Knock down of ATGL decreased basal lipolysis but did not change catecholamine-stimulated lipolysis. Treatment of hMSC with a selective HSL inhibitor during and/or after differentiation in adipocytes reduced basal lipolysis by 50%, but stimulated lipolysis was inhibited completely. In contrast to findings in rodents, ATGL is of less importance than HSL in regulating catecholamine-induced lipolysis and cannot replace HSL when this enzyme is continuously inhibited. However, both lipases regulate basal lipolysis in human adipocytes. ATGL expression, unlike HSL, is not influenced by obesity or PCOS.     

Increased norepinephrine by medium-chain triglyceride attributable to lipolysis in white and brown adipose tissue of C57BL/6J mice

A further investigation of the lipolysis induced by medium-chain triglyceride (MCT) was conducted on C57BL/6J mice fed with a diet containing 2% MCT or 2% long-chain triglyceride (LCT). Blood norepinephrine, body fat and blood lipid variables, and the protein or mRNA expression of the genes relevant to lipolysis were measured and analyzed in the white and brown adipose tissue (WAT, BAT). Decreased body fat and improved blood lipid profiles attributable to MCT were confirmed. A higher level of blood norepinephrine was observed with the MCT diet. The adipose triglyceride lipase (ATGL) activity and its mRNA expression, the expression of protein and mRNA of the beta 3 adrenergic receptor (β3-AR) in both WAT and BAT, and the hormone-sensitive lipase (HSL) activity and its mRNA expression in BAT were significantly increased in the mice with MCT feeding. The lipolysis induced by MCT might be partially mediated by increasing norepinephrine, thereafter signaling the up-regulation of β3-AR, ATGL, and HSL in WAT and BAT.     

The FTO gene is associated with adulthood obesity in the Mexican population

Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.     

High-fat diet elevates resting intramuscular triglyceride concentration and whole body lipolysis during exercise

This study determined the role of intramuscular triglyceride (IMTG) and adipose lipolysis in the elevated fat oxidation during exercise caused by a high-fat diet. In four separate trials, six endurance-trained cyclists exercised at 50% peak O2 consumption for 1 h after a two-day control diet (22% fat, CON) or an isocaloric high-fat diet (60% fat, HF) with or without the ingestion of acipimox, an adipose lipolysis inhibitor, before exercise. During exercise, HF elevated fat oxidation by 72% and whole body lipolysis [i.e., the appearance rate of glycerol in plasma (Ra glycerol)] by 79% compared with CON (P < 0.05), and this was associated with a 36% increase (P < 0.05) in preexercise IMTG concentration. Although acipimox lowered plasma free fatty acid (FFA) availability, HF still increased fat oxidation and Ra glycerol to the same magnitude above control as the increase caused by HF without acipimox (i.e., both increased fat oxidation 13-14 micromol.kg(-1).min(-1)). In conclusion, the marked increase in fat oxidation after a HF diet is associated with elevated IMTG concentration and whole body lipolysis and does not require increased adipose tissue lipolysis and plasma FFA concentration during exercise. This suggests that altered substrate storage in skeletal muscle is responsible for increased fat oxidation during exercise after 2 days of an HF diet.     

In vivo nitric oxide suppression of lipolysis in subcutaneous abdominal adipose tissue is greater in obese than lean women

Mounting evidence suggests there is a reduced mobilization of stored fat in obese compared to lean women. It has been suggested that this decreased lipid mobilization may lead to, or perpetuate, the obese state; however, there may be a beneficial effect of reduced lipolysis, either by allowing for a sink of excess fatty acids, or by limiting a potentially harmful rise in interstitial and circulating fatty acid concentration. Nitric oxide (NO) may be responsible for a portion of the reduced in vivo rates of lipolysis in obese women because NO reduces adipose tissue lipolysis and adipose tissue nitric oxide synthase (NOS) mRNA is higher in obese than lean individuals. The purpose of this study was to determine if the inhibition of NOS by L-N(g)-monomethyl-L-arginine (L-NMMA) in the absence and presence of lipolytic stimulation would result in a larger increase in lipolytic rate in obese (OB) than lean (LN) women. Microdialysis probes were inserted into the subcutaneous abdominal adipose tissue of seven obese and six lean women to monitor lipolysis. Dialysate glycerol concentration increased in response to L-NMMA in OB (basal 125 ± 26 μmol/l; L-NMMA 225 ± 35 μmol/l) to a greater extent than in LN (basal 70 ± 18 μmol/l; L-NMMA 84 ± 20 μmol/l) women (P < 0.05). Dialysate glycerol increased to a similar extent in OB and LN in response to adrenergic stimulation by isoprenaline or norepinephrine in the presence of L-NMMA. The differential glycerol responses to L-NMMA between obese and lean could not be explained by differential blood flow responses. It can be concluded that NO suppresses basal lipolysis in obese women to a greater extent than in lean women.     

Metabolic patterns and insulin responsiveness of enlarging fat cells

The rate and pattern of glucose metabolism, basal lipolysis, and intracellular concentration of free fatty acids were determined in isolated epididymal fat cell preparations (mean volume 30-800 pl) from rats on the basis of fat cell number and in relation to the cell volume. The effects of increasing glucose concentrations in the medium and of insulin on the cellular metabolic activities were compared. Expanding fat cell volume correlated positively and significantly (P < 0.001) with the synthesis of glyceride glycerol from glucose (correlation coefficient, r = 0.919), with rates of basal lipolysis (r = 0.663), and with intracellular free fatty acid accumulation (r = 0.796); it correlated negatively and significantly with glucose conversion to glyceride fatty acids (r = -0.814, P < 0.01). The differences in patterns of glucose metabolism and basal lipolysis between small (<100 pl) and large (>400 pl) fat cells were not modified by insulin or by increments in glucose concentration. The results indicate that the reduced capacity of the large fat cells to respond to insulin cannot be attributed solely to a limited capacity of the cells to take up and metabolize increasing amounts of glucose. The acquired unresponsiveness of the large cells to insulin may result from an alteration in the mechanism of action of insulin and may be related to an intracellular metabolic derangement with increased basal lipolysis, free fatty acid accumulation, and accelerated glyceride synthesis resulting from the accumulation of triglyceride.     

The 20-kD human growth hormone reduces body fat by increasing lipolysis and decreasing lipoprotein lipase activity

AIM: The aim of this study was to estimate the lipolytic activity of the human growth hormone variant, 20-kD human growth hormone (20K-hGH). METHODS: Obese KV-A(y) mice were given daily subcutaneous injections of 20K-hGH (0.25, 0.5, 1.0 mg/kg), 22K-hGH (0.25 mg/kg) or saline as a control for 2 weeks. Body composition (fat, water and protein), lipolysis and lipoprotein lipase (LPL) activity were measured 24 h after the final injection. RESULTS: Both growth hormone isoforms significantly reduced relative fat pad and whole body lipids. In addition, 20K-hGH produced an inhibition of LPL activity in adipose tissue and stimulated lipolysis in adipocytes. CONCLUSION: These data strongly suggest that inhibition of LPL activity in adipose tissue and stimulation of lipolysis in adipocytes by 20K-hGH treatment reduce adipose tissue mass, resulting in body fat reduction.     

Effects of the G-protein beta3 subunit 825T allele on adipogenesis and lipolysis in cultured human preadipocytes and adipocytes.

The recently discovered C825T polymorphism of the G-protein beta 3 subunit has been reported to be associated with the development of hypertension and obesity. The aim of our study was to investigate the relationship between the C825T polymorphism and functional aspects of human adipose cells, particularly with regard to adipose differentiation and lipolysis. Adipose tissue samples were collected from 65 women with a BMI ranging from 19.7 to 39.7 kg/m 2 undergoing surgical mammary reduction. The stromal cells were allowed to undergo differentiation in primary culture using adipogenic media of defined composition. No significant difference was observed between the CC carriers and the carriers of the T allele under all adipogenic conditions with differentiation capacity related to the genotype. In a subgroup of patients (n = 20), lipolysis in isolated fat cells was determined by measurement of glycerol in the culture medium upon catecholamine exposure. Glycerol release after 10(-7) mmol/l isoproterenol was significantly higher in fat cells from the 10 CC carriers than in adipocytes from the T allele carriers when expressed as percentage of basal glycerol release (increase above baseline: CC: 809 +/- 174 %, T allele carriers: 247 +/- 88 %, p = 0.01), while basal glycerol concentrations were no different according to genotype after controlling for either age or BMI. In conclusion, this study provides the first evidence that the GNB3 825T allele is associated with an impairment of the beta-adrenergic control of lipolysis.     

Heredity and changes in body composition and adipose tissue metabolism after short-term exercise-training

The purpose of the experiment was to investigate the genotype dependency of body composition and adipose tissue metabolism following short-term exercise-training. Six pairs of male, sedentary monozygotic twins took part in a 22 day ergocycle training program at 58% VO2max, with a mean exercise duration of 116 min x day-1. Body weight, fat mass, percent body fat and VO2max, were evaluated before and after the training program. From a suprailiac region fat biopsy, the following adipose tissue metabolic variables were evaluated: fat cell diameter, basal and epinephrine stimulated lipolysis, basal and insulin stimulated lipogenesis from glucose and heparin releasable lipoprotein lipase activity. The exercise-training program increased (p less than 0.01) VO2max and decreased (p less than 0.01) body weight, fat mass and percent body fat. Variation in response within twin pairs was not significantly different than response between pairs in the aforementioned variables. However, a significant within pair resemblance (p less than 0.01) for changes in fat free mass was observed. Adipose tissue metabolic indicators exhibited a large interindividual variation in response to exercise-training. Significant within twin pair resemblance was observed only for basal lipogenesis. Moreover, the non significant within twin pair resemblance for changes in body fat and adipose tissue metabolic indicators suggests that heredity is not a major factor influencing changes in body fat and adipose tissue indicators to short-term training resulting in negative energy balance. Changes in fat free mass were, however, closely coupled to the genotype.     

Regulation of PPARgamma but not obese gene expression by dietary fat supplementation

Leptin, the product of the obese gene, and peroxisome proliferator activated receptor gamma (PPARgamma) are important regulators of energy metabolism, adipogenesis, and immune function. In rodent models, both genes seem to respond at the mRNA and/or protein levels to dietary fat consumption. To determine the effect(s) of dietary saturated and polyunsaturated fatty acids on the expression (mRNA abundance) of these genes, adipose tissue was obtained from pigs fed three different dietary fat sources. Corn-soybean meal diets containing no added fat (NO, control) or 10% beef tallow (BT), safflower oil (SO), or fish oil (FO) were fed ad libitum (n = 12) for 12 weeks. The abundance of obese, PPARgamma1, and PPARgamma2 mRNA was quantified relative to 18S rRNA using ribonuclease protection assays. The gain:feed ratio was improved (P < 0.05) 21% by all fats with a corresponding reduction (P < 0.05) in feed intake. Relative to pigs fed NO, serum total cholesterol was increased (P < 0.01) in pigs fed BT and triglyceride and nonesterified fatty acid concentrations were increased (P < 0.01) by all supplemental fats. Serum insulin was increased (P < 0.10) only by SO. Neither obese nor PPARgamma1 mRNA abundance were responsive to added fat (P > 0.15). However, the abundance of PPARgamma2 mRNA was increased fourfold by SO compared with the NO diet. These data indicate that the abundance of obese mRNA is independent of dietary fat consumption per se, whether saturated or unsaturated, when feed consumption is reduced due to greater dietary caloric density. Furthermore, we provide evidence that expression of the PPARgamma2 gene in porcine adipose tissue is selectively responsive to SO (presumably linoleic acid, 18:2n-6).     

Inverse regulation of basal lipolysis in perigonadal and mesenteric fat depots in mice

Given the strong link between visceral adiposity and (hepatic) insulin resistance as well as liver steatosis, it is crucial to characterize obesity-associated alterations in adipocyte function, particularly in fat depots drained to the liver. Yet these adipose tissues are not easily accessible in humans, and the most frequently studied depot in rodents is the perigonadal, which is drained systemically. In the present study, we aimed to study alterations in lipolysis between mesenteric and perigonadal adipocytes in mice. Basal free fatty acid and glycerol release was significantly lower in perigonadal compared with mesenteric adipocytes isolated from chow-fed C57BL/6J mice. However, this difference completely vanished in high-fat diet-fed mice. Consistently, protein levels of the G(0)/G(1) switch gene 2 (G0S2), which were previously found to be inversely related to basal lipolysis, were significantly lower in mesenteric compared with perigonadal fat of chow-fed mice. Similarly, perilipin was differently expressed between the two depots. In addition, adipocyte-specific overexpression of G0S2 led to significantly decreased basal lipolysis in mesenteric adipose tissue of chow-fed mice. In conclusion, lipolysis is differently regulated between perigonadal and mesenteric adipocytes, and these depot-specific differences might be explained by altered regulation of G0S2 and/or perilipin.     

Hormone-sensitive lipase-independent adipocyte lipolysis during beta-adrenergic stimulation, fasting, and dietary fat loading

In white adipose tissue, lipolysis can occur by hormone-sensitive lipase (HSL)-dependent or HSL-independent pathways. To study HSL-independent lipolysis, we placed HSL-deficient mice in conditions of increased fatty acid flux: beta-adrenergic stimulation, fasting, and dietary fat loading. Intraperitoneal administration of the beta(3)-adrenergic agonist CL-316243 caused a greater increase in nonesterified fatty acid level in controls (0.33 +/- 0.05 mmol/l) than in HSL(-/-) mice (0.12 +/- 0.01 mmol/l, P < 0.01). Similarly, in isolated adipocytes, lipolytic response to CL-316243 was greatly reduced in HSL(-/-) mice compared with controls. Fasting for 相似文献