Lipolytic Products Research Articles

Products of lipolysis in human milk destroy parasites.

Journal Article Products of Lipolysis in Human Milk Destroy Parasites Get access Nutrition Reviews, Volume 45, Issue 10, October 1987, Pages 236–238, https://doi.org/10.1111/j.1753-4887.1987.tb02687.x Published: 01 October 1987

Inflammation associated with the postprandial lipolysis of triglyceriderich lipoproteins by lipoprotein lipase

Although hypertriglyceridemia has repeatedly been implicated as an atherogenic condition, there are conflicting reports concerning the atherogenicity of products released from triglyceride-rich lipoproteins by lipoprotein lipase. The hydrolysis of triglyceride is a normal process by which chylomicrons and very low-density lipoproteins are metabolized and cleared from the circulation, which would suggest a beneficial role for lipoprotein lipase in reducing circulating levels of triglyceride and, therefore, reducing atherosclerotic burden. However, many in vitro studies have shown that lipolysis products such as fatty acids induce vascular cell inflammation, which can initiate or exacerbate atherosclerosis. This review summarizes the results and implications of recent studies on the effects of lipoprotein lipase on vascular inflammation, expanding upon existing controversy among human postprandial studies, animal models, and in vitro experimental models.

Postprandial Evolution in Composition and Characteristics of Human Duodenal Fluids in Different Nutritional States

The purpose of this study was to assess the changes in duodenal composition in three nutritional states: fasted, fed, and fat-enriched fed state. Two isocaloric meals were administered to healthy subjects on nonconsecutive days. Subsequently, duodenal samples were collected every 30min after which they were characterized with respect to pH, lipolytic products, bile salts, phospholipids, osmolality, and surface tension. The resulting time profiles displayed fluctuating patterns, which reflect high inter- and intrasubject variability. Duodenal composition was not altered by the higher fat percentage of the fat-enriched liquid meal. Monoglycerides, amounting from 5% to 88% of total lipids, were the dominant lipolytic species, followed by free fatty acids. Within 30min after meal administration, individual intraduodenal concentrations of lipid products were 0.0–5.5, 1.0–14.9, and 3.1–22.4mg/mL in fasted, fed, and fat-enriched fed state, respectively. The corresponding values for bile salts were 2.0–9.0, 6.9–9.3, and 4.4–30.3mM and for phospholipids 0.06–2.4, 2.6–5.7, and 1.4–9.3mM, respectively. Specific trends though, were not detected. This study illustrates the variable intraluminal conditions that can result after food intake. As intraduodenal events (e.g., intraduodenal dissolution) affect absorption of poorly water soluble and/or highly lipophilic drugs, this variability may possibly contribute to the highly variable drug plasma-time profiles often observed.

CHANGES IN FREE FATTY ACID AND DIACYLGLYCEROL COMPOUNDS IN SHORT‐RIPENING DRY‐CURED SAUSAGE

ABSTRACT A study on lipolysis of Southern Italy short‐ripened dry‐cured sausages manufactured without and with starters was carried out. Samples were submitted to microbiological and chemical analysis during drying and ripening, whereas sensory analysis was performed at the end of the ripening. The starters, addition caused the inhibition of the Enterobacteriaceae. An increase of free fatty acids (FFAs) and diacylglycerols (DAGs) during the ripening was observed. The addition of starter did not affect FFA and DAG release. The DAG profile including 1,2‐ and 1,3‐isomers was analyzed for the first time in dry‐cured sausages. Oleic, linoleic and palmitic acids, and 1,2‐, 1,3‐palmitinolein, 1,2‐ and 1,3‐diolein were the most abundant compounds in FFA and DAG, respectively. A decrease in the concentration of some 1,2‐DAG and an increase of 1,3‐OO and 1,3‐OP species during the process was observed. Finally, the addition of starter cultures slightly influenced the sensory properties of sausages.PRACTICAL APPLICATIONSIn this work the development and application of an analytical method for the determination of free fatty acids (FFAs) and diacylglycerols (DAGs) in sausages was achieved. DAGs are intermediate products of hydrolysis and also constitute a substrate for hydrolysis reactions leading to FFA release. These latter compounds undergo a series of reactions leading to the formation of low‐molecular‐weight products responsible for sensory properties of dry‐cured sausages. Therefore, the assessment of these lipolysis products is a useful tool for evaluating the ripening process of dry‐cured sausages.

Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation

Triglyceride-rich lipoprotein (TGRL) lipolysis products provide a pro-inflammatory stimulus that can alter endothelial barrier function. To probe the mechanism of this lipolysis-induced event, we evaluated the pro-inflammatory potential of lipid classes derived from human postprandial TGRL by lipoprotein lipase (LpL). Incubation of TGRL with LpL for 30 min increased the saturated and unsaturated FFA content of the incubation solutions significantly. Furthermore, concentrations of the hydroxylated linoleates 9-hydroxy ocatadecadienoic acid (9-HODE) and 13-HODE were elevated by LpL lipolysis, more than other measured oxylipids. The FFA fractions elicited pro-inflammatory responses inducing TNFalpha and intracellular adhesion molecule expression and reactive oxygen species (ROS) production in human aortic endothelial cells (HAECs). The FFA-mediated increase in ROS was blocked by both the cytochrome P450 2C9 inhibitor sulfaphenazole and NADPH oxidase inhibitors. Compared with linoleate, 13-HODE was found to be a more potent inducer of ROS production in HAECs, an activity that was insensitive to both NADPH oxidase and cytochrome P450 inhibitors. Therefore, although the oxidative metabolism of FFA in endothelial cells can produce inflammatory responses, TGRL lipolysis can also release preformed mediators of oxidative stress (e.g., HODEs) that may influence endothelial cell function in vivo by stimulating intracellular ROS production.

Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells

Apoptosis and underlying mechanisms were evaluated in human umbilical vein endothelial cells (HUVECs), in target tissues of late diabetic vascular complications [human aortic endothelial cells (HAECs) and human retinal endothelial cells (HRECs)], and in endothelial progenitor cells (EPCs) exposed to FFAs, which are elevated in obesity and diabetes. Saturated stearic acid concentration dependently induced apoptosis that could be mediated via reduced membrane fluidity, because both apoptosis and membrane rigidity are counteracted by eicosapentaenoic acid. PUFAs triggered apoptosis at a concentration of 300 micromol/l in HUVECs, HAECs, and EPCs, but not HRECs, and, in contrast to stearic acid, involved caspase-8 activation. PUFA-induced apoptosis, but not stearic acid-induced apoptosis, strictly correlated (P < 0.01) with protein expression of E2F-1 (r = 0.878) and c-myc (r = 0.966). Lack of c-myc expression and activity owing to quiescence or transfection with dominant negative In373-Myc, respectively, renders HUVECs resistant to PUFA-induced apoptosis. Because c-myc is abundant in growing cells only, apoptosis triggered by PUFAs, but not by saturated stearic acid, obviously depends on the growth/proliferation status of the cells. Finally, this study shows that FFA-induced apoptosis depends on the vascular origin and growth/proliferation status of endothelial cells, and that saturated stearic acid-induced apoptosis and PUFA-induced apoptosis are mediated via different mechanisms.

Colloidal Structures in Media Simulating Intestinal Fed State Conditions with and Without Lipolysis Products

To study the ultrastructure of biorelevant media and digestion products of self-nanoemulsifying drug delivery system (SNEDDS) at high level BS/PL conditions. Cryogenic transmission electron microscopy (Cryo-TEM) was employed to visualize the colloid structures in the biorelevant media and lipolytic products generated during hydrolysis of a SNEDDS formulation. Their electrical properties were investigated by measuring their zeta-potential values. In the biorelevant media, vesicles (either unilamellar or multilamellar) and bilayer fragments are visualized. Occasionally, vesicles with an internal deformed structure are recognized, suggesting surface tension or uneven lateral stress. Visualization studies of the intermediate colloidal phases produced during digestion of a SNEDDS using the in vitro lipolysis model revealed the formation of similar structures as previously reported. The zeta-potential of the media was negatively charged and decreased from -23 to -35 mV with increasing surfactant/lipid load. Lower zeta-potential values (-16 mV) obtained for the structures formed during the lipid hydrolysis of the SNEDDS were probably due to the presence of calcium, which shields the surface, thereby reducing the charge. The diversity of these vesicles in terms of size, lamellarity, and internal organization advocate their important role during lipid digestion in the gastrointestinal milieu.

Comparative study of lipolysis by PLA 2 of DOPC substrates organized as monolayers, bilayer vesicles and nanocapsules

The water-soluble lipolytic enzymes act at the interface of insoluble lipid substrates, where the catalytical step is coupled with various interfacial phenomena as enzyme penetration, solubilization of reaction products, loss of mechanical stability of organized assemblies of phospholipids molecule, etc. One biologically relevant example is the enzymatic hydrolysis of DOPC by PLA 2, which results in cleavage of phospholipids molecules into water insoluble lipolytic products, namely oleic acid and lysophospholipid. In general, the enzymatic activity depends on the substrate organization and molecular environment of the catalytic reaction. The lipolysis by phospholipase A 2 of dioleoylphosphatidylcholine substrates organized as monolayer, bilayers vesicles and lipid nanocapsules was studied by measuring the decrease of the surface area at constant surface pressure or increase of the surface pressure at constant area at air–water interface. A kinetic model describing the coupling of the catalytic act with corresponding interfacial phenomena was developed. By using the kinetic model the values for the global hydrolytic kinetic constants were obtained. The obtained value for the monolayer is five orders of magnitude higher than this obtained with small unilamellar vesicles and six orders of magnitude higher then those obtained with lipid nanocapsules. The comparison shows that the enzymatic catalytic act occurring in the lipid environment of the monolayer is more efficacious than at the vesicle and nanocapsules interfaces.

Synergistic Effect ofVespaAmino Acid Mixture on Lipolysis in Rat Adipocytes

The effect of Vespa amino acid mixture (VAAM) on the release of lipolytic products was examined in isolated rat adipocytes. Concentrations of 112.5 to 225 ppm of VAAM showed significantly greater release of non-esterified fatty acids (NEFA) and glycerol than the same concentrations of casein amino acid mixture (CAAM). The integrated relative release of NEFA and glycerol was lower in response to individual administration of amino acids comprising VAAM than to VAAM itself. Further, amino acids mixtures deficient in a single amino acid comprising VAAM showed significantly lower release of lipolytic products than VAAM. These data suggest that the synergistic effect of VAAM on the release of lipolytic products is a function of concurrent exposure to the unique composition of amino acids found in VAAM as compared to the effect of exposure to the same individual un-mixed amino acids or to a mixture lacking one of the amino acids comprising VAAM.

Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action by inhibition of cAMP-phosphodiesterase (PDE)

The present study investigated the lipolytic (break of fat stored) effect of a citrus-based polyphenolic dietary supplement (SINETROL) at human adipocytes (ex vivo), body fat (clinical) and biochemical levels (inhibition of phosphodiesterase). Free fatty acids (FFA) release was used as indicator of human adipocyte lipolysis and SINETROL activity has been compared with known lipolytic products (isoproterenol, theopylline and caffeine). SINETROL stimulated significantly the lipolytic activity in a range of 6 fold greater than the control. Moreover, SINETROL has 2.1 greater activity than guarana 12% caffeine while its content in caffeine is 3 times lower. Clinically, two groups of 10 volunteers with BMI relevant of overweight were compared during 4 and 12 weeks with 1.4 g/day SINETROL and placebo supplementation. In the SINETROL Group the body fat (%) decreased with a significant difference of 5.53% and 15.6% after 4 and 12 weeks, respectively, while the body weight (kg) decreased with a significant difference of 2.2 and 5.2 kg after 4 and 12 weeks, respectively. These observed effects are linked to SINETROL polyphenolic composition and its resulting synergistic activity. SINETROL is a potent inhibitor of cAMP-phosphodiesterase (PDE) (97%) compared to other purified compounds (cyanidin-3 glycoside, narangin, caffeine). These results suggest that SINETROL has a strong lipolytic effect mediated by cAMP-PDE inhibition. SINETROL may serve to prevent obesity by decreasing BMI.

Competition between Lipases and Monoglycerides at Interfaces

Tensiometry (the pendant drop technique), interfacial shear rheology, and ellipsometry have been used to study the effect of polar lipids that are generated during fat digestion on the behavior of lipases at the oil-water interface. Both Sn-1,3 regiospecific and nonregiospecific lipases have been used, and a noncatalytically active protein, beta-lacloglobulin, has been used as reference in the interfacial shear rheology experiments. The results from the pendant drop measurements and the interfacial rheology studies were in agreement with each other and demonstrated that the Sn-2 monoglyceride, which is one of the lipolysis products generated when a Sn-1,3 regiospecific lipase catalyzes triglyceride hydrolysis, is very interfacially active and efficiently expels the enzyme from the interface. Ellipsometry conducted at the liquid-liquid interface showed that the lipase forms a sublayer in the aqueous phase, just beneath the monoglyceride-covered interface. Sn-1/3 monoglycerides do not behave this way because they are rapidly degraded to fatty acid and glycerol and the fatty acid (or the fatty acid salt) does not have enough interfacial activity to expel the lipase from the interface. Since the lipases present in the gastrointestinal tract are highly Sn-1,3 regiospecific, we believe that the results obtained can be transferred to the in vivo situation. The formation of stable and amphiphilic Sn-2 monoglycerides can be seen as a self-regulatory process for fat digestion.

Hydrolysis of Acyl‐Homogeneous and Fish Oil Triacylglycerols Using Desalted Midgut Extract from Atlantic Salmon, Salmo salar

Despite several studies aimed at evaluating the positional and fatty acid specificity of fish triacylglycerol (TAG) digestive lipases, there is still much uncertainty regarding these issues. The aim of the present study was therefore to address these questions in Atlantic salmon (Salmo salar L.). Crude luminal midgut extracts were collected from fed salmon and the hydrolysis studied for various substrates including triolein (Tri-18:1), trilinolein (Tri-18:2), trilinolenin (Tri-18:3), trieicosapentaenoin (Tri-20:5), tridocosahexaenoin (Tri-22:6) and natural fish oil TAG. Using Tri-18:1, in a time-curve model showed an initial high degree of sn-1 or sn-3 specificity where sn-1,2(2,3)-diacylglycerol (1,2(2,3)-DAG) and free fatty acid (FFA) were the main hydrolytic products up to 15 min. Lack of initial sn-2 specificity was confirmed by negligible sn-1,3-diacylglycerol (1,3-DAG) being produced. During the further hydrolysis of DAG, all positions appeared susceptible to attack causing a concomitantly small increase in sn-1(3)-monoacylglycerol (1(3)-MAG) and 2-MAG, but not at the level expected for an exclusively sn-1,3-specific lipase. Oleic acid (18:1n-9) and eicosapentaenoic acid (20:5n-3) were preferred substrates for hydrolysis using both fish oil and acyl-homogeneous TAGs with FFA as the main product of lipolysis. Hydrolysis of the natural fish oil TAG appeared slower yet produced proportionally more MAG and DAG after 5 min, and similar specificities, as for synthetic TAG substrates, were exhibited with 18:1n-9 and 20:5n-3 accumulating in the FFA fraction after 30 min. Notably, 16:0 was particularly conserved in MAG. As TAG resynthesis of absorbed lipid in salmon enterocytes proceeds preferably with 2-MAG as templates, the absorption of 2-MAG, produced during initial stages of TAG hydrolysis, would need to occur rapidly to be effectively utilised via the MAG pathway.

Product Composition, Structure, and Bioavailability

Bioavailability is the fraction of an administered dose that reaches the systemic circulation. Health claims for functional foods can only be made if the ingredient reaches the target site to trigger the physiological action, hence substantiation requires good bioavailability. This is also expressed in the European Regulation on Health Claims. Albeit not new at all, a full understanding of the controlling factors for bioavailability in foods is still lacking. Foods are complex systems and can be part of a meal. The impact of product composition and the interplay with human physiology during fed or fasted state has to be understood: a functional ingredient has to be released from the product matrix into a molecularly dispersed state, either in classic solution or in micellar state. Only in the dispersed state can actives cross the gut wall. Release and dissolution are depending on both molecular physicochemical properties of the active and those of the entire product. More complex is the uptake of hydrophobic, poorly water-soluble substrates. As they do not dissolve in the aqueous intestinal environment, presence of fat, release of bile, enzymes, and gut motility to induce lipolysis are required. Surface-active bile salts together with lipolysis products create micelles containing the hydrophobic active. This imposes limitations on the formulation space for hydrophobic compounds. Finally, many ingredients are not fit for straightforward use as they compromise the stability or sensory characteristics of the product. Compartmentalization strategies, like encapsulation, may offer solutions to the problem; it should, however, not be forgotten that encapsulates themselves may effect bioavailability through the changed dynamics of the uptake processes. To explore and build a better understanding of these factors, a range of models are available and used in product formulation and claim substantiation. A structured approach and the selection of proper models will help to improve functional food formulations in the future.

Enhancing effect of Labrafac Lipophile WL 1349 on oral bioavailability of hydroxysafflor yellow A in rats

The objective of the present investigation was to clarify the mechanism by which Labrafac Lipophile WL 1349 (WL 1349) enhanced the oral bioavailability (BA) of hydroxysafflor yellow A (HSYA), the representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drug. HSYA–phospholipid complex was prepared, and dissolved into WL 1349 with a certain surfactant to form a stable oil solution. Oral administration of HSYA aqueous solution at a dosage of 4.5 mg/kg resulted a low plasma HSYA concentration with C max and AUC 0–8 h values of 0.105 μg/ml and 10.29 μg min/ml, respectively. HSYA–phospholipid complex oil solution with the same administration and dosage increased the plasma HSYA concentration significantly with C max and AUC 0–8 h values of 2.063 μg/ml and 381.145 μg min/ml, respectively. The results showed that WL 1349 could improve oral absorption of HSYA remarkably. Bioavailability investigations were performed to show WL 1349 dosage independent from HSYA absorption within the dosage from 1 ml/kg to 9 ml/kg. The test of bile duct ligation in rats showed that the oil solution containing WL 1349 did not result in detectable plasma HSYA concentration, but HSYA aqueous solution had the same AUC 0–8 h as the bile duct was not ligated. The in vitro lipolysis experiments of WL 1349 showed that WL 1349 was emulsified by deoxycholate, and then was hydrolyzed to fatty acids and monoglycerides by pancreatic lipase rapidly. The lipolysis products of WL 1349, caprylic acid, capric acid and caprylic and capric acid monoglycerides all improved the BA of HSYA in vivo. The results above indicated the emulsifying by bile, and hydrolysis to fatty acids and monoglycerides by pancreatic lipase was one of the enhancing mechanisms of HSYA–phospholipid complex oil solution absorption.

Differential effects of apoE3‐ and apoE4‐associated VLDL lipolysis products on monocyte activation

Atherosclerosis is an inflammatory condition perpetuated by the activation and recruitment of circulating monocytes. Postprandial lipemia, characterized by elevated triglyceride‐rich lipoproteins such as very low‐density lipoproteins (VLDL), has been implicated as a mechanism of chronic vascular injury. We hypothesized that postprandial VLDL lipolysis products (PVLP) would induce a greater inflammatory response from monocytes than fasting VLDL lipolysis products (FVLP), mediated by apoE isoform changes in the postprandial state. VLDL was isolated from human donors, subjected to lipolysis, and treated in combination with LPS on THP‐1 monocytes. We found that FVLP attenuated LPS‐induced TNFα secretion to a greater extent than PVLP. This was partially reversed by blocking apoE on FVLP, but not on PVLP. In addition, apoE3‐containing vesicles attenuated LPS‐induced TNFα and IL‐1β expression, while complexes with apoE4 increased cytokine expression. An apoE ELISA revealed that apoE3 binds to LPS with higher affinity than apoE4, suggesting that apoE3 can sequester LPS away from monocytes more readily, thus attenuating their activation. These results imply that postprandial changes in apoE structure and isoform on VLDL could have dramatic effects on vascular inflammation, with implications for atherogenesis. This work was supported by the Training Program in Biomolecular Technology (T32‐GM08799).

Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound

The usefulness of selected biorelevant dissolution media (BDM) to predict in vivo drug absorption was studied. Dissolution profiles of solid formulations of a poorly soluble model compound were compared in BDM simulating fasted and two levels of fed state. A non-physiologically relevant medium containing the cationic surfactant, cetrimide, was also investigated. All the media studied were capable of differentiating between the formulations employed, with formulation A consistently ranking high and formulations C and D ranking low. An in vivo dog study was carried out and an attempt was made to obtain a level A correlation between the plasma absorption curves and in vitro dissolution curves, using non-linear regression software. The in vitro–in vivo correlation (IVIVC) models developed indicated that fed state media (BDM 3) containing high levels of both bile salts (BS) and lipolysis products (LP) were best able to predict in vivo pharmacokinetic parameters ( C max and AUC) with prediction errors lower than 10%. Overall, design and use of appropriate media for in vitro dissolution is extremely important. This study demonstrates the potential of physiologically relevant media containing both BS and LP for use in formulation and early drug development.

Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice

Apolipoprotein B (apoB)-containing lipoproteins play a critical role in whole body lipid homeostasis and the pathogenesis of atherosclerosis. The assembly of hepatic apoB-containing lipoproteins, VLDL, is governed by the availability of lipids, including triacylglycerol (TG). The majority of TG associated with VLDL is derived from the hepatic cytoplasmic lipid stores by a process involving lipolysis followed by reesterification. Microsomal triacylglycerol hydrolase (TGH) has been demonstrated to play a role in the lipolysis/reesterification process. To evaluate the potential regulatory role of TGH in hepatic VLDL assembly, we developed inducible transgenic mice expressing a human TGH minigene under the control of the mouse metallothionein promoter. Induction of human TGH by zinc resulted in liver-specific expression of the enzyme associated with 3- to 4-fold increases in lipolytic activity that could be attenuated with a TGH-specific inhibitor. Augmented TGH activity led to increased secretion of newly synthesized apoB and plasma TG levels. These results suggest that increased hepatic expression of TGH leads to a more proatherogenic plasma lipid and apoB profile.

Preliminary Analysis of the Lipase Gene (gehM) Expression of Staphylococcus xylosus In Vitro and during Fermentation of Naturally Fermented Sausages (In Situ)

Coagulase-negative catalase-positive cocci (CNCPC) play a very important role during the fermentation of sausages. In particular, they are involved in the aroma formation of the final product, because they release lipases that are able to free short-chain fatty acids that are contributing to the sensory characteristics of the fermented sausage. Few studies have been undertaken to elucidate the regulation of lipase gene expression in Staphylococcus xylosus by substrate molecules or products of lipolysis. The aim of this study was to analyze the gehM gene expression of S. xylosus DSMZ 6179 in vitro with growth media containing different concentrations of lipids and in situ during the maturation of fermented sausages. The results obtained suggest that a concentration that increases in triglycerides in the growth medium suppresses the expression of the lipase gene.

Adipose Tissue Metabolism - An Aspect We Should not Neglect?

Free fatty acids (FFAs) are the most metabolically important products of adipose tissue lipolysis. Experimentally creating high FFA concentrations can reproduce the metabolic abnormalities of obesity in lean, healthy persons and lowering FFA concentrations can improve the metabolic health of upper body obese individuals. FFA concentrations are determined by both the release of FFAs into the bloodstream and the clearance of FFAs from the bloodstream. Normal FFA release rates are different in men and women and total FFA release is closely linked to resting energy expenditure. Upper body subcutaneous fat, visceral fat, and leg fat depots contribute differently to the exposure of various tissues to FFAs. The implications of regional adipose tissue lipolysis to systemic FFA availability and the effect of different approaches to treatment of obesity are discussed.

Differential Activation of the Sympathetic Innervation of Adipose Tissues by Melanocortin Receptor Stimulation

Melanocortins are implicated in the control of energy intake/expenditure. Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. Melanocortin-4 receptor (MC4-R) mRNA is expressed on sympathetic nervous system (SNS) outflow neurons to white adipose tissue (WAT) in Siberian hamsters, suggesting a role in lipid mobilization. Therefore, we tested whether third ventricular injections of MTII increased sympathetic drive to WAT and interscapular brown adipose tissue (IBAT) using norepinephrine turnover (NETO) as a measure of sympathetic drive. We also tested for MTII-induced changes in lipolysis-related WAT gene expression (beta3-adrenoceptors, hormone sensitive lipase) and IBAT thermogenesis (beta3-adrenoceptor, uncoupling protein-1). Finally, we tested whether third ventricularly injected MTII, a highly selective MC4-R agonist (cyclo[beta-Ala-His-D-Phe-Arg-Trp-Glu]NH2) increased or agouti-related protein decreased IBAT temperature in hamsters implanted with sc IBAT temperature transponders. Centrally administered MTII provoked differential sympathetic drives to WAT and IBAT (increased inguinal WAT, dorsosubcutaneous WAT and IBAT NETO, but not epididymal WAT and retroperitoneal WAT NETO). MTII also increased circulating concentrations of the lipolytic products free fatty acids and glycerol but not plasma catecholamines, suggesting lipid mobilization via WAT SNS innervation and not via adrenal medullary catecholamines. WAT or IBAT gene expression was largely unaffected by acute MTII treatment, but IBAT temperature was increased by MTII and the MC4-R agonist and decreased by agouti-related protein. Collectively, this is the first demonstration of central melanocortin agonist stimulation of WAT lipolysis through the SNS and confirms melanocortin-induced changes in BAT thermogenesis.