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PubMed1998

Chronic ethanol consumption induces the production of tumor necrosis factor-alpha and related cytokines in liver and adipose tissue.

Increases in monocyte/macrophage production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), parallel the evolution of liver injury in rats and humans with alcoholic liver disease. However, the possibility that TNF-alpha expression may be induced in other cell populations before serious liver disease develops has not been evaluated. To clarify this issue, mRNAs and/or protein levels of TNF-alpha and cytokines [interleukin (IL)-6, IL-10, transforming growth factor-beta (TGF)-beta, IL-12, and interferon-gamma] that regulate its biological activity were measured in sera, liver, and adipose tissues of rats that had developed hepatic steatosis after consuming ethanol-containing diets for 6 weeks. Cytokine expression in the ethanol-fed groups was compared with that of pair-fed controls rats that had received isocaloric amounts of a similar, ethanol-free diet for the same time period. Animals were studied both before and after a surgical stress (partial hepatectomy) that is known to provoke cytokine production. Chronic ethanol consumption led to increased serum concentrations of TNF and related cytokines, at least in part, by inducing the overproduction of these factors in the liver and peripheral adipose tissues. Despite the pair-feeding protocol that ensured similar calorie consumption in both groups, adipose tissues in ethanol-fed rats also expressed more leptin, a TNF-alpha-inducible mRNA that encodes an appetite-suppressing hormone. Thus, white adipose tissue can be an important source of cytokines in nonobese animals and may be a target for ethanol's actions. These data implicate TNF-alpha as a potential mediator of the nutritional-metabolic aberrations that often accompany chronic alcohol intake, even in the absence of advanced liver disease.

Adipose Tissue↗
PubMed1993

Adipose tissue cholesteryl ester transfer protein mRNA in response to probucol treatment: cholesterol and species dependence.

Probucol treatment results in an increase in plasma concentrations of cholesteryl ester transfer protein (CETP) which may account, in part, for the effects of this agent on plasma concentrations of HDL cholesterol. We have examined the mechanism by which probucol increases plasma CETP and have determined the associated changes in the plasma distribution of high density lipoprotein (HDL) particles. Studies were carried out in nine hypercholesterolemic subjects and five normal volunteers. Probucol treatment resulted in a 31% increase in plasma concentrations of CETP and a 23% decrease in HDL cholesterol (P < 0.01). The plasma concentration of LpA-I decreased by 40% (P < 0.01) whereas no change occurred in the LpA-I/A-II subclass of HDL. Plasma CETP increased significantly by 1 week of therapy and remained stable over 10 to 14 weeks of therapy. In spite of the significant increase in plasma concentrations of CETP, the abundance of CETP mRNA in peripheral adipose tissue decreased markedly (P < 0.001). These results suggested that probucol may alter CETP synthesis in another tissue such as liver or, alternatively, may have other effects on CETP secretion into or catabolism out of the plasma pool. Further studies were carried out in hamsters because, in this species, adipose tissue is a major site and liver is a negligible site for CETP synthesis. Hamsters were fed probucol with or without dietary cholesterol because this species was previously shown to respond to dietary cholesterol with an increase in adipose tissue mRNA levels and in plasma CETP concentrations, thus providing the opportunity to determine whether probucol would alter these parameters independently of the dietary cholesterol effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1990

Beta-adrenoceptor expression in human fat cells from different regions.

The expression of beta-adrenoceptors (BAR) was investigated in abdominal and gluteal fat cells of 32 nonobese men and women using radioligand binding and RNA excess solution hybridization. In both sexes the number of BAR binding sites was about twice as high in abdominal as in gluteal fat cells (P less than 0.01). Northern blot analysis of total RNA from adipose tissue showed hybridization of the BAR1 probe to an mRNA species of about 2.5 kb and of the BAR2 probe to an mRNA species of approximately 2.2 kb. The steady-state mRNA levels of BAR 1 and BAR 2 were also about twice as high in abdominal as in gluteal adipocytes of men and women (P less than 0.01). In abdominal fat cells the mRNA levels were approximately 45 and 30 molecules/cell for BAR1 and BAR2, respectively. There were no regional or sex variations in BAR 1 and BAR 2 mRNA stability. The apparent half-life of mRNA for both receptor subtypes was approximately 6 h in both regions. The mRNA levels for beta actin did not differ between the two regions in either sex. Thus, differences in expression of the genes encoding for BAR 1 and BAR 2 can explain why abdominal fat cells have more BAR than gluteal fat cells. This variation in gene expression may be a molecular mechanism underlying the well known regional differences in catecholamine-induced lipolysis activity between central and peripheral adipose tissue.

Adipose Tissue↗
PubMed2004

Effects of androgen therapy on adipose tissue and metabolism in older men.

We investigated the effects of oxandrolone on regional fat compartments and markers of metabolism. Thirty-two 60- to 87-yr-old men (body mass index, 28.1 +/- 3.4 kg/m(2)) were randomized to oxandrolone (20 mg/d; n = 20) or matching placebo (n = 12) treatment for 12 wk. Oxandrolone reduced total (-1.8 +/- 1.0 kg; P < 0.001), trunk (-1.2 +/- 0.6 kg; P < 0.001), and appendicular (-0.6 +/- 0.6 kg; P < 0.001) fat, as determined by dual energy x-ray absorptiometry. The changes in total and trunk fat were greater (P < 0.001) than the changes with placebo. By magnetic resonance imaging, visceral adipose tissue decreased (-20.9 +/- 12 cm(2); P < 0.001), abdominal sc adipose tissue (SAT) declined (-10.7 +/- 12.1 cm(2); P = 0.043), the ratio VAT/SAT declined from 0.57 +/- 0.23 to 0.49 +/- 0.19 (P = 0.002), and proximal and distal thigh SC fat declined [-8.3 +/- 6.7 cm(2) (P < 0.001) and -2.2 +/- 3.0 kg (P = 0.004), respectively]. Changes in proximal and distal thigh SC fat with oxandrolone were different than with placebo (P = 0.018 and P = 0.059). A marker of insulin sensitivity (quantitative insulin sensitivity check index) improved with oxandrolone by 0.0041 +/- 0.0071 (P = 0.018) at study wk 12. Changes in total fat, abdominal SAT, and proximal extremity SC fat were correlated with changes in fasting insulin from baseline to study wk 12 (r >or= 0.45; P < 0.05). Losses of total fat and SAT were greater in men with baseline testosterone of 10.4 nmol/liter or less (<or= 300 ng/dl) than in those with higher levels [-2.5 +/- 1.1 vs. -1.5 +/- 0.8 kg (P = 0.036) and -24.1 +/- 14.3 vs. -2.9 +/- 21.3 cm(2) (P = 0.03), respectively]. Twelve weeks after discontinuing oxandrolone, 83% of the reductions in total, trunk, and extremity fat by dual energy x-ray absorptiometry scanning were sustained (P < 0.02). Androgen therapy, therefore, produced significant and durable reductions in regional abdominal and peripheral adipose tissue that were associated with improvements in estimates of insulin sensitivity. However, high-density lipoprotein cholesterol decreased by -0.49 +/- 0.21 mmol/liter and directly measured low-density lipoprotein cholesterol increased by 0.57 +/- 0.67 mmol/liter and non-high-density lipoprotein cholesterol increased by 0.54 +/- 0.97 mmol/liter (P < 0.03 for each) during treatment with oxandrolone; these changes were largely reversible. Thus, therapy with an androgen that does not adversely affect lipids may be beneficial for some components of the metabolic syndrome in overweight older men with low testosterone levels.

Adipose Tissue↗
PubMed2001

Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy.

Human immunodeficiency virus (HIV) lipodystrophy (LIPO) is characterized by increased visceral adiposity, peripheral fat atrophy, dyslipidemia, and insulin resistance. GH concentrations are known to vary inversely with excess weight and body fat but have not been investigated in HIV lipodystrophy. Twenty-one subjects with HIV LIPO, 20 HIV-infected nonlipodystrophy subjects (NONLIPO), and 20 control (C) subjects were prospectively recruited for this study and compared. Subjects in the three groups were all male, age-matched [median, 47 yr old (interquartile range, 37-50) LIPO; 41 (37-44) NONLIPO; and 43 (37-49) C], and body mass index-matched [median, 24.3 kg/m(2) (interquartile range, 22.2-26.6) LIPO; 24.4 (23.3-25.9) NONLIPO; and 24.8 (22.7-26.1) C] (P: > 0.05 for all comparisons). Visceral abdominal fat [16,124 mm(2) (11,246-19,790) LIPO; 7,559 (5,134-11,201) NONLIPO; and 8,803 (6,165-11,623) C; P < 0.01 LIPO vs. NONLIPO and LIPO vs. C] and the ratio of visceral abdominal fat to sc abdominal fat [1.37 (0.71-2.44) LIPO vs. 0.57 (0.47-0.78) NONLIPO vs. 0.55 (0.41-0.71) C, P < 0.01 LIPO vs. NONLIPO and LIPO vs. C] were significantly increased in the LIPO subjects but were not significantly different between NONLIPO and C. The mean overnight GH concentration, determined from frequent sampling every 20 min (from 2000 h to 0800 h) was decreased in the LIPO subjects [0.38 microg/L (0.13-0.67) LIPO vs. 0.96 (0.53-1.30) NONLIPO vs. 0.81 (0.49-1.03) C, P < 0.05 LIPO vs. NONLIPO and LIPO vs. C] and not significantly different between NONLIPO and C. Pulse analysis demonstrated decreased baseline GH [0.08 microg/L (0.06-0.21) LIPO vs. 0.19 (0.10-0.32) NONLIPO vs. 0.17 (0.12-0.57) C, P < 0.05 LIPO vs. NONLIPO and LIPO vs. C] and GH peak amplitude [1.06 microg/L (0.46-1.94) LIPO vs. 2.47 (1.22-3.43) NONLIPO and 2.27 (1.36-4.25) C, P < 0.05 LIPO vs. NONLIPO and LIPO vs. C] in the LIPO subjects but no significant difference in pulse frequency. No significant differences were observed between NONLIPO and C for any GH parameter. Insulin-like growth factor-I was not different between the groups. Total body fat (r = -0.40, P = 0.01) and visceral fat (r = -0.58, P = 0.0001) correlated inversely with mean overnight GH concentrations in the HIV-infected patients. In a multivariate regression model, controlling for age, body mass index, body fat, and visceral fat, only visceral fat was a significant predictor of mean GH concentrations (P = 0.0036, r(2) for model = 0.40). These data demonstrate normal GH pulse frequency and insulin-like growth factor-I concentrations but reduced mean GH concentrations, basal GH concentrations, and GH pulse amplitude in patients with HIV lipodystrophy. Increased visceral adiposity is the strongest predictor of reduced GH concentrations in HIV lipodystrophy. Further studies are necessary to determine the clinical significance of reduced GH in patients with HIV lipodystrophy.

Abdomen↗
PubMed2006

Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Previous studies suggest that obesity is related to increased risk of renal cell carcinoma (RCC); however, only a few studies report on measures of central vs. peripheral adiposity. We examined the association between anthropometric measures, including waist and hip circumference and RCC risk among 348,550 men and women free of cancer at baseline from 8 countries of the European Prospective Investigation into Cancer and Nutrition (EPIC). During 6.0 years of follow-up we identified 287 incident cases of RCC. Relative risks were calculated using Cox regression, stratified by age and study center and adjusted for smoking status, education, alcohol consumption, physical activity, menopausal status, and hormone replacement therapy use. Among women, an increased risk of RCC was conferred by body weight (relative risk [RR] in highest vs. lowest quintile = 2.13; 95% confidence interval [CI] = 1.16-3.90; p-trend = 0.003), body mass index (BMI) (RR = 2.25; 95% CI = 1.14-4.44; p-trend = 0.009), and waist (RR = 1.67; 95% CI = 0.94-2.98; p-trend = 0.003) and hip circumference (RR = 2.30; 95% CI = 1.22-4.34; p-trend = 0.01); however, waist and hip circumference were no longer significant after controlling for body weight. Among men, hip circumference (RR = 0.44; 95% CI = 0.20-0.98; p-trend = 0.03) was related significantly to decreased RCC risk only after accounting for body weight. Height was not related significantly to RCC risk. Our findings suggest that obesity is related to increased risk of RCC irrespective of fat distribution among women, whereas low hip circumference is related to increased RCC risk among men. Our data give further credence to public health efforts aiming to reduce the prevalence of obesity to prevent RCC, in addition to other chronic diseases.

Body Composition↗
PubMed1985

Estimating radiofrequency power deposition in body NMR imaging.

Simple theoretical estimates of the average, maximum, and spatial variation of the radiofrequency power deposition (specific absorption rate) during hydrogen nuclear magnetic resonance imaging are deduced for homogeneous spheres and for cylinders of biological tissue with a uniformly penetrating linear rf field directed axially and transverse to the cylindrical axis. These are all simple scalar multiples of the expression for the cylinder in an axial field published earlier (Med. Phys. 8, 510 (1981]. Exact solutions for the power deposition in the cylinder with axial (Phys. Med. Biol. 23, 630 (1978] and transversely directed rf field are also presented, and the spatial variation of power deposition in head and body models is examined. In the exact models, the specific absorption rates decrease rapidly and monotonically with decreasing radius despite local increases in rf field amplitude. Conversion factors are provided for calculating the power deposited by Gaussian and sinc-modulated rf pulses used for slice selection in NMR imaging, relative to rectangular profiled pulses. Theoretical estimates are compared with direct measurements of the total power deposited in the bodies of nine adult males by a 63-MHz body-imaging system with transversely directed field, taking account of cable and NMR coil losses. The results for the average power deposition agree within about 20% for the exact model of the cylinder with axial field, when applied to the exposed torso volume enclosed by the rf coil. The average values predicted by the simple spherical and cylindrical models with axial fields, the exact cylindrical model with transverse field, and the simple truncated cylinder model with transverse field were about two to three times that measured, while the simple model consisting of an infinitely long cylinder with transverse field gave results about six times that measured. The surface power deposition measured by observing the incremental power as a function of external torso radius was comparable to the average value. This is consistent with the presence of a variable thickness peripheral adipose layer which does not substantially increase surface power deposition with increasing torso radius. The absence of highly localized intensity artifacts in 63-MHz body images does not suggest anomalously intense power deposition at localized internal sites, although peak power is difficult to measure.

Humans↗
PubMed1998

Fat metabolism in exercise.

Fatty acids are the most abundant source of endogenous energy substrate. They can be mobilized from peripheral adipose tissue and transported via the blood to active muscle. During higher intensity exercise, triglyceride within the muscle can also be hydrolyzed to release fatty acids for subsequent direct oxidation. Control of fatty acid oxidation in exercise can potentially occur via changes in availability, or via changes in the ability of the muscle to oxidize fatty acids. We have performed a series of experiments to distinguish the relative importance of these potential sites of control. The process of lipolysis normally provides free fatty acids (FFA) at a rate in excess of that required to supply resting energy requirements. At the start of low intensity exercise, lipolysis increases further, thereby providing sufficient FFA to provide energy substrates in excess of requirements. However, lipolysis does not increase further as exercise intensity increases, and fatty acid oxidation becomes approximately equal to the total amount of fatty acids available at 65% of VO2 max. When plasma FFA concentration is increased by lipid infusion during exercise at 85% VO2 max, fat oxidation is significantly increased. Taken together, these observations indicate that fatty acid availability can be a determinant of the rate of their oxidation during exercise. However, even when lipid is infused well in excess of requirements during high-intensity exercise, less than half the energy is derived from fat. This is because the muscle itself is a major site of control of the rate of fat oxidation during exercise. We have demonstrated that the mechanism of control of fatty acid oxidation in the muscle is the rate of entry into the mitochondria. We hypothesize that the rate of glycolysis is the predominant regulator of the rate of carbohydrate metabolism in muscle, and that a rapid rate of carbohydrate oxidation caused by mobilization of muscle glycogen during high intensity exercise inhibits fatty acid oxidation by limiting transport into the mitochondria. During low intensity exercise, glycogen breakdown and thus glycolysis is not markedly stimulated, so the increased availability of fatty acids allows their oxidation to serve as the predominant energy source. At higher intensity exercise, stimulation of glycogen breakdown and glycolysis cause increased pyruvate entry into the TCA cycle for oxidation, and as a consequence the inhibition of fatty acid oxidation by limiting their transport into the mitochondria.

Animals↗
PubMed1985

Influence of a low molecular weight serine proteinase inhibitor (camostate) on lipolysis of isolated adipocytes.

The effect of the epsilon-guanidino acid derivate camostate (FOY 305) on lipolysis of isolated adipocytes was evaluated to test its supposed influence on the reactions of lipid metabolism in experimental shock. Isoprenaline (10(-6) M) and theophylline (10(-3) M) significantly stimulated lipolysis in vitro. The basal submaximal (isoprenaline 10(-6)-10(-9) M) and maximal (isoprenaline 10(-6) M) catecholamine-stimulated lipolysis were not affected by camostate (10(-6) M). Furthermore, camostate (0.1-100 X 10(-6) M) did not influence half-maximal theophylline-induced lipolysis of the adipocytes. Our findings do not support the suggestion that epsilon-guanidino acid derivatives diminish in shock the increase of free fatty acids in blood via an influence on lipolysis in the peripheral adipose tissue.

Adipose Tissue↗
PubMed1995

Reduction of hyperlipidemia in hepatoma-bearing rats by dietary fish oil.

The effect of dietary fish oil on serum lipid levels was studied by comparing it with dietary corn oil in Donryu rats subcutaneously implanted with an ascites hepatoma cell line (AH109A). The hepatoma-bearing rats exhibited hyperlipidemia characterized by a rise in both serum cholesterol and triglyceride levels. Increased cholesterogenesis in the host liver and decreased steroid excretion into feces are suggested to be responsible for the hepatoma-induced hypercholesterolemia, and increased fatty acid mobilization from peripheral adipose tissues and decreased triglyceride clearance from the blood circulation are considered causes for the hepatoma-induced hypertriglyceridemia. Dietary fish oil reduced the hyperlipidemia in these animals, suppressed the hepatoma-induced increase in hepatic cholesterogenesis and fatty acid mobilization from adipose tissue. Dietary fish oil also tended to increase fatty acid oxidation in the liver. Such diverse effects of fish oil may lead to the reduction of the hepatoma-induced hyperlipidemia. These results suggest that studies on dietary fish oil may be warranted in patients with cancer-related hyperlipidemia.

Animals↗
PubMed1994

Effects of low casein and fish oil on hyperlipidemia and proteinuria in nephritic rats.

The effects of amino acid-fortified low casein and fish oil (FO) diets on hyperlipidemia and proteinuria were studied in rats with nephrotoxic serum nephritis. After an antiserum injection, rats were maintained for 14 d on four different experimental diets: a 20% casein diet containing corn oil (CO) or FO, or an 8% casein diet supplemented with cystine plus threonine containing CO or FO. The 8% casein diets reduced urinary protein excretion in nephritic rats without inducing severe growth retardation or fatty liver compared with the basal 20% casein diets. Both the 8% casein diet and the FO diet decreased serum cholesterol, triglyceride and phospholipid levels in nephritic rats, and nonesterified fatty acid levels were decreased by FO feeding. In nephritic animals, hepatic cholesterol synthesis was decreased by the 8% casein diets compared with the 20% casein diets, and tended to be reduced by FO feeding between groups at the same casein levels. No effect of diet was observed on fatty acid synthesis among the nephritic rats. FO administration to the nephritic animals suppressed fecal steroid excretion. While lipoprotein lipase activity was unchanged among the nephritic rats, hepatic triglyceride lipase activity was reduced by either the 8% casein or FO diet. The results suggest that the hypolipidemic action of low casein diets may, at least in part, be due to reduced hepatic cholesterol synthesis and suppressed triglyceride secretion from the liver. They also suggest that the hypolipidemic action of FO may, at least in part, be due to reduced hepatic cholesterol synthesis and decreased fatty acid mobilization from peripheral adipose tissue.

Animal Feed↗
PubMed1998

Relevance of individual characteristics for human heat stress response is dependent on exercise intensity and climate type.

Multiple heterogeneous groups of subjects (both sexes and a wide range of maximal oxygen uptake VO2max, body mass, body surface area (AD),% body fat, and AD/mass coefficient) exercised on a cycle ergometer at a relative (%VO2max, REL) or an absolute (60 W) exercise intensity in a cool (CO 21 degrees C, 50% relative humidity), warm humid (WH 35 degrees C, 80%) and a hot dry (HD 45 degrees C, 20%) environment. Rectal temperature (Tre) responses were analysed for the influence of the individual's characteristics, environment and exercise intensity. Exposures consisted of 30-min rest, followed by 60-min exercise. The Tre was negatively correlated with mass in all conditions. Body mass acted as a passive heat sink in all the conditions tested. While negatively correlated with VO2max and VO2max per kilogram body mass in most climates, Tre was positively correlated with VO2max and VO2max per kilogram body mass in the WH/REL condition. Thus, when evaporative heat loss was limited as in WH, the higher heat production of the fitter subjects in the REL trials determined Tre and not the greater efficiency for heat loss associated with high VO2max. Body fatness significantly affected Tre only in the CO condition, where, with low skin blood flows (measured as increases in forearm blood flow), the insulative effect of fat was pronounced. In the warmer environments, high skin blood flows offset the resistance offered by peripheral adipose tissue. Contrary to other studies, Tre was positively correlated with AD/mass coefficient for all conditions tested. For both exercise types used, being big (a high heat loss area and heat capacity) was apparently more beneficial from a heat strain standpoint than having a favourable AD/mass coefficient (high in small subjects). The total amount of variance in Tre responses which could be attributed to individual characteristics was dependent on the climate and the type of exercise. Though substantial for absolute exercise intensities (52%-58%) the variance explained in Tre differed markedly for relative intensities: 72% for the WH climate with its limited evaporative capacity, and only 10%-26% for the HD and CO climates. The results showed that individual characteristics play a significant role in determining the responses of body core temperature in all conditions tested, but their contribution was low for relative exercise intensities when evaporative heat loss was not restricted. This study demonstrated that effects of individual characteristics on human responses to heat stress cannot be interpreted without taking into consideration both the heat transfer properties of the environment and the metabolic heat production resulting from the exercise type and intensity chosen. Their impact varies substantially among conditions.

Adipose Tissue↗
PubMed1992

The role of the sympathetic nervous system in promoting liver cirrhosis induced by carbon tetrachloride, using the essential hypertensive animal (SHR).

The effects of the sympathetic nervous system on liver injury induced experimentally by carbon tetrachloride (CCl4) were examined in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). It was found that the SHR had an elevated catecholamine (CA) content in the adrenal gland without any treatment, and fluorescence histochemistry also revealed dense adrenergic innervations in the liver. Moreover, the SHR showed greater sensitivity to CCl4 stimulation in the sympathetic nervous system than the WKY, resulting in a decreased hepatic blood flow in the acute stage and a depleted CA in the adrenal gland, a lowered blood pressure (BP) and a released non-esterified fatty acid (NEFA) from peripheral adipose tissue in the chronic stage. Upon repetition of the CCl4 treatments twice a week for 4 weeks, the liver injury was more severe in the SHR than in the WKY. Plasma glutamate-pyruvate transaminase (GPT) activity was increased in both strains but more significantly in the SHR than in the WKY. Histological examination of the liver in the SHR showed established cirrhosis, whereas only bridging fibrosis was seen in the WKY. These results suggest that the pathogenesis of the liver damage induced by CCl4 in the SHR, is attributable to the enhanced response of the sympathetic nervous system that releases massive amounts of CA which then lead to vasoconstriction and metabolic changes that promote liver damage.

Animals↗
PubMed2004

[Body-weight regulation in children: a key to obesity physiopathology understanding].

Body weight is regulated within a narrow, individualized range despite large daily caloric mismatches. This process which maintains a stable level of body weight is known as adipostat. Peripheral adiposity signals, mainly leptin and ghrelin, communicate the status of energy stores in the body to the hypothalamus, which in turn coordinates adaptive responses to energy imbalances via reciprocal alterations in appetite and energy expenditure. Obese individuals also display behavioral and metabolic adjustments to weight perturbations as if their adipostat attempts to maintain their elevated body-weight. Efforts to reduce the weight of obese subjects from the elevated levels they ordinarily display are frequently ineffective because their adipostat actively resists by stimulating appetite and reducing energy expenditure. These adaptive responses to weight loss may be an explanation to understand the traditional failure of obesity treatment. Strategy of directly altering the energy-regulating system may be a promising therapeutic approach.

Body Weight↗
PubMed2006

Dirty dealing: hepatic vagal afferents reshuffle fat distribution.

To evaluate the role of hepatic peroxisome-proliferator-activated receptor (PPAR) gamma 2 in the control of energy balance, Uno and colleagues examined the metabolic effects of overexpression of PPAR gamma 2 selectively in mouse and rat liver. Mice demonstrated a surprising degree of hepatic steatosis accompanied by significant reductions in peripheral adiposity. This crosstalk between liver and adipose tissue appears to be mediated by both the sensory component of the hepatic vagus nerve and sympathetic efferents. These data suggest a novel hepatic-adipose neuraxis that regulates the distribution of stored fat.

Adipose Tissue↗
PubMed2003

Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression.

Leptin-deficient ob/ob mice show many characteristics of obesity, including excess peripheral adiposity as well as severe hepatic steatosis, at least in part, due to increased hepatic lipogenesis. Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) alpha but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein (SREBP)-1. We have previously shown that the disruption of SREBP-1 in ob/ob mice decreased their liver triglyceride storage. To examine whether PUFAs could reduce hepatic triglyceride deposition, we challenged ob/ob mice with dietary PUFA. It is demonstrated that PUFA markedly decreased the mature form of SREBP-1 protein and thereby reduced the expression of lipogenic genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) in the livers of ob/ob mice. Consequently, the liver triglyceride content and plasma alanine aminotransferase (ALT) levels were decreased. Furthermore, both hyperglycemia and hyperinsulinemia in ob/ob mice were improved by PUFA administration, similar to the effect of PPARalpha activators. In conclusion, PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPARalpha.

Alanine Transaminase↗
PubMed2006

Serotonin reciprocally regulates melanocortin neurons to modulate food intake.

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

Animals↗
PubMed2004

Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man.

Maintaining a stable body weight set-point is assumed to rely on a homeostatic central nervous system (CNS) regulation of body fat with the particular involvement of hypothalamic pathways. The peripheral adiposity signals insulin and leptin convey information on the amount of energy stored as body fat to the arcuate nucleus of the hypothalamus, where anabolic/orexigenic and catabolic/anorexigenic pathways interact to regulate food intake and energy expenditure. One of the most prominent orexigenic messengers is neuropeptide Y (NPY), whereas melanocortins, including alpha-melanocyte-stimulating hormone (alpha-MSH), are essential for inducing anorexigenic effects. The melanocortin receptor 4 (MC4-R) plays the most important role in mediating catabolic effects of alpha-MSH. In this review, we present a series of own studies on NPY, insulin and MSH/ACTH4-10, an MC4-R agonist. The studies were all based on the intranasal route of administration which enables a direct access of the peptides to hypothalamic functions. NPY acutely attenuated electrocortical signs of meal-related satiety. Prolonged intranasal administration of insulin as well as of MSH induced weight loss in healthy human subjects. However, overweight subjects did not lose body fat after MSH administration. The results corroborate in humans the significance of all three messengers for the central nervous regulation of adiposity and might contribute to the future development of medical strategies against body-weight-related disorders.

Administration, Intranasal↗