OBJECTIVES: Obesity is a frequent metabolic disorder but an effective therapy is still scarce. Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity but are ineffective after peripheral application. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice. RESULTS: Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF-2 receptor. Peripheral administration of myristoylated and palmitoylated PrRP analogs to fasted mice induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight and improved metabolic parameters, and attenuated lipogenesis in mice with diet-induced obesity. CONCLUSIONS: Our data suggest that the lipidization of PrRP enhances stability and mediates its effect in central nervous system. Strong anorexigenic and body-weight-reducing effects make lipidized PrRP an attractive candidate for anti-obesity treatment.

• MeSH
• Energy Metabolism MeSH
• Prolactin-Releasing Hormone analogs & derivatives   pharmacology   MeSH
• Anti-Obesity Agents pharmacology   MeSH
• Lipids chemistry   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity prevention & control   MeSH
• Half-Life MeSH
• Eating MeSH
• Appetite Regulation MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Prolactin-Releasing Hormone MeSH
• Anti-Obesity Agents MeSH
• Lipids MeSH

AIMS/HYPOTHESIS: Intake of n-3 polyunsaturated fatty acids reduces adipose tissue mass, preferentially in the abdomen. The more pronounced effect of marine-derived eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on adiposity, compared with their precursor alpha-linolenic acid, may be mediated by changes in gene expression and metabolism in white fat. METHODS: The effects of EPA/DHA concentrate (6% EPA, 51% DHA) admixed to form two types of high-fat diet were studied in C57BL/6J mice. Oligonucleotide microarrays, cDNA PCR subtraction and quantitative real-time RT-PCR were used to characterise gene expression. Mitochondrial proteins were quantified using immunoblots. Fatty acid oxidation and synthesis were measured in adipose tissue fragments. RESULTS: Expression screens revealed upregulation of genes for mitochondrial proteins, predominantly in epididymal fat when EPA/DHA concentrate was admixed to a semisynthetic high-fat diet rich in alpha-linolenic acid. This was associated with a three-fold stimulation of the expression of genes encoding regulatory factors for mitochondrial biogenesis and oxidative metabolism (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [Ppargc1a, also known as Pgc1alpha] and nuclear respiratory factor-1 [Nrf1] respectively). Expression of genes for carnitine palmitoyltransferase 1A and fatty acid oxidation was increased in epididymal but not subcutaneous fat. In the former depot, lipogenesis was depressed. Similar changes in adipose gene expression were detected after replacement of as little as 15% of lipids in the composite high-fat diet with EPA/DHA concentrate, while the development of obesity was reduced. The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells. CONCLUSIONS/INTERPRETATION: The anti-adipogenic effect of EPA/DHA may involve a metabolic switch in adipocytes that includes enhancement of beta-oxidation and upregulation of mitochondrial biogenesis.

• MeSH
• Epididymis drug effects   metabolism   MeSH
• NF-E2-Related Factor 1 drug effects   genetics   MeSH
• Carnitine O-Palmitoyltransferase drug effects   genetics   MeSH
• Cells, Cultured MeSH
• alpha-Linolenic Acid pharmacology   MeSH
• Eicosapentaenoic Acid pharmacology   MeSH
• Docosahexaenoic Acids pharmacology   MeSH
• Lipogenesis drug effects   MeSH
• Mitochondrial Proteins drug effects   metabolism   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Fatty Acids, Unsaturated isolation & purification   metabolism   pharmacology   MeSH
• Obesity prevention & control   MeSH
• Oxidation-Reduction MeSH
• Subcutaneous Fat drug effects   metabolism   MeSH
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
• Gene Expression Regulation drug effects   MeSH
• Fish Oils chemistry   MeSH
• Trans-Activators drug effects   genetics   MeSH
• Transcription Factors MeSH
• Adipose Tissue drug effects   metabolism   MeSH
• Adipocytes drug effects   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• NF-E2-Related Factor 1 MeSH
• Carnitine O-Palmitoyltransferase MeSH
• alpha-Linolenic Acid MeSH
• Eicosapentaenoic Acid MeSH
• Docosahexaenoic Acids MeSH
• Mitochondrial Proteins MeSH
• Fatty Acids, Unsaturated MeSH
• Ppargc1a protein, mouse MeSH Browser
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
• Fish Oils MeSH
• Trans-Activators MeSH
• Transcription Factors MeSH

Omega-3 PUFA of marine origin reduce adiposity in animals fed a high-fat diet. Our aim was to learn whether EPA and DHA could limit development of obesity and reduce cellularity of adipose tissue and whether other dietary FA could influence the effect of EPA/DHA. Weight gain induced by composite high-fat diet in C57BL/6J mice was limited when the content of EPA/DHA was increased from 1 to 12% (wt/wt) of dietary lipids. Accumulation of adipose tissue was reduced, especially of the epididymal fat. Low ratio of EPA to DHA promoted the effect. A higher dose of EPA/DHA was required to reduce adiposity when admixed to diets that did not promote obesity, the semisynthetic high-fat diets rich in EFA, either alpha-linolenic acid (ALA, 18:3 n-3, the precursor of EPA and DHA) or linoleic (18:2 n-6) acid. Quantification of adipose tissue DNA revealed that except for the diet rich in ALA the reduction of epididymal fat was associated with 34-50% depression of tissue cellularity, similar to the 30% caloric restriction in the case of the high-fat composite diet. Changes in plasma markers and adipose gene expression indicated improvement of lipid and glucose metabolism due to EPA/DHA even in the context of the diet rich in ALA. Our results document augmentation of the antiadipogenic effect of EPA/DHA during development of obesity and suggest that EPA/DHA could reduce accumulation of body fat by limiting both hypertrophy and hyperplasia of fat cells. Increased dietary intake of EPA/DHA may be beneficial regardless of the ALA intake.

• MeSH
• Diet MeSH
• Mice MeSH
• Fatty Acids, Unsaturated therapeutic use   MeSH
• Obesity diet therapy   etiology   pathology   MeSH
• Fatty Acids, Omega-3 therapeutic use   MeSH
• Adipose Tissue pathology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fatty Acids, Unsaturated MeSH
• Fatty Acids, Omega-3 MeSH

In vitro experiments suggest that stimulation of lipolysis by catecholamines in adipocytes depends on the energy status of these cells. We tested whether mitochondrial uncoupling proteins (UCPs) that control the efficiency of ATP production could affect lipolysis and noradrenaline signalling in white fat in vivo. The lipolytic effect of noradrenaline was lowered by ectopic UCP1 in white adipocytes of aP2-Ucp1 transgenic mice, overexpressing the UCP1 gene from the aP2 gene promoter, reflecting the magnitude of UCP1 expression, the impaired stimulation of cAMP levels by noradrenaline and the reduction of the ATP/ADP ratio in different fat depots. Thus only subcutaneous but not epididymal fat was affected. UCP1 also down-regulated the expression of hormone-sensitive lipase and lowered its activity, and altered the expression of trimeric G-proteins in adipocytes. The adipose tissue content of the stimulatory G-protein alpha subunit was increased while that of the inhibitory G-protein alpha subunits decreased in response to UCP1 expression. Our results support the idea that the energy status of cells, and the ATP/ADP ratio in particular, modulates the lipolytic effects of noradrenaline in adipose tissue in vivo. They also demonstrate changes at the G-protein level that tend to overcome the reduction of lipolysis when ATP level in adipocytes is low. Therefore, respiratory uncoupling may exert a broad effect on hormonal signalling in adipocytes.

• MeSH
• Adenosine Diphosphate metabolism   MeSH
• Adenosine Triphosphate metabolism   MeSH
• Cyclic AMP metabolism   MeSH
• DNA Primers MeSH
• Genotype MeSH
• Hepatocytes enzymology   MeSH
• Ion Channels MeSH
• Lipase genetics   MeSH
• Lipolysis * MeSH
• Membrane Proteins genetics   physiology   MeSH
• Mitochondrial Proteins MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Norepinephrine metabolism   MeSH
• GTP-Binding Proteins metabolism   MeSH
• Gene Expression Regulation, Enzymologic MeSH
• Base Sequence MeSH
• Carrier Proteins genetics   physiology   MeSH
• Adipose Tissue enzymology   metabolism   MeSH
• Uncoupling Protein 1 MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Diphosphate MeSH
• Adenosine Triphosphate MeSH
• Cyclic AMP MeSH
• DNA Primers MeSH
• Ion Channels MeSH
• Lipase MeSH
• Membrane Proteins MeSH
• Mitochondrial Proteins MeSH
• Norepinephrine MeSH
• GTP-Binding Proteins MeSH
• Carrier Proteins MeSH
• Ucp1 protein, mouse MeSH Browser
• Uncoupling Protein 1 MeSH