GPR10 and neuropeptide FF receptor 2 (NPFFR2) play important role in the regulation of food intake and energy homeostasis. Understanding the interaction between these receptors and their specific ligands, such as prolactin-releasing peptide, is essential for developing stable peptide analogs with potential for treating obesity. By breeding and characterizing double knockout (dKO) mice fed standard or high-fat diet (HFD), we provide insights into the metabolic regulation associated with the GPR10 and NPFFR2 deficiency. Both WT and dKO mice were subjected to behavioral tests and an oral glucose tolerance test. Moreover, dual-energy X-ray absorptiometry (DEXA) followed by indirect calorimetry were performed to characterize dKO mice. dKO mice of both sexes, when exposed to an HFD, showed reduced glucose tolerance, hyperinsulinemia, and insulin resistance compared with controls. Moreover, they displayed increased liver weight with worsened hepatic steatosis. Mice displayed significantly increased body weight, which was more pronounced in dKO males and caused by higher caloric intake on a standard diet, while dKO females displayed obesity characterized by increased white adipose tissue and enhanced hepatic lipid accumulation on an HFD. Moreover, dKO females exhibited anxiety-like behavior in the open field test. dKO mice on a standard diet had a lower respiratory quotient, with no significant changes in energy expenditure. These results provide insights into alterations associated with disrupted GPR10 and NPFFR2 signaling, contributing to the development of potential anti-obesity treatment.

• Keywords
• GPR10/NPFFR2-deficient mice, double KO mice, impaired glucose utilization, insulin resistance, obesity,
• MeSH
• Adipose Tissue, White metabolism   MeSH
• Diet, High-Fat * adverse effects   MeSH
• Energy Metabolism genetics   MeSH
• Insulin Resistance MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout * MeSH
• Mice MeSH
• Obesity * metabolism   genetics   MeSH
• Prediabetic State * metabolism   genetics   MeSH
• Receptors, Neuropeptide * genetics   metabolism   deficiency   MeSH
• Receptors, G-Protein-Coupled * genetics   metabolism   deficiency   MeSH
• Sex Factors MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• neuropeptide FF receptor MeSH Browser
• Receptors, Neuropeptide * MeSH
• Receptors, G-Protein-Coupled * MeSH

OBJECTIVE: Classical ATP-independent non-shivering thermogenesis enabled by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is activated, but not essential for survival, in the cold. It has long been suspected that futile ATP-consuming substrate cycles also contribute to thermogenesis and can partially compensate for the genetic ablation of UCP1 in mouse models. Futile ATP-dependent thermogenesis could thereby enable survival in the cold even when brown fat is less abundant or missing. METHODS: In this study, we explore different potential sources of UCP1-independent thermogenesis and identify a futile ATP-consuming triglyceride/fatty acid cycle as the main contributor to cellular heat production in brown adipocytes lacking UCP1. We uncover the mechanism on a molecular level and pinpoint the key enzymes involved using pharmacological and genetic interference. RESULTS: ATGL is the most important lipase in terms of releasing fatty acids from lipid droplets, while DGAT1 accounts for the majority of fatty acid re-esterification in UCP1-ablated brown adipocytes. Furthermore, we demonstrate that chronic cold exposure causes a pronounced remodeling of adipose tissues and leads to the recruitment of lipid cycling capacity specifically in BAT of UCP1-knockout mice, possibly fueled by fatty acids from white fat. Quantification of triglyceride/fatty acid cycling clearly shows that UCP1-ablated animals significantly increase turnover rates at room temperature and below. CONCLUSION: Our results suggest an important role for futile lipid cycling in adaptive thermogenesis and total energy expenditure.

• Keywords
• Brown adipose tissue, Fatty acids, Futile substrate cycle, Lipolysis, Re-esterification, UCP1-independent thermogenesis,
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Adipose Tissue, Brown * metabolism   MeSH
• Fatty Acids metabolism   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Thermogenesis * MeSH
• Triglycerides metabolism   MeSH
• Uncoupling Protein 1 genetics   metabolism   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
• Adenosine Triphosphate MeSH
• Fatty Acids MeSH
• Triglycerides MeSH
• Ucp1 protein, mouse MeSH Browser
• Uncoupling Protein 1 MeSH

Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs-pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)-regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.

• Keywords
• adipocytes, glucose homeostasis, insulin, lipogenesis, obesity,
• MeSH
• Adipose Tissue, White metabolism   MeSH
• Diet, High-Fat MeSH
• Hypoglycemic Agents pharmacology   MeSH
• Lipogenesis drug effects   MeSH
• Fatty Acids metabolism   MeSH
• Lipid Metabolism drug effects   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Obese MeSH
• Mice MeSH
• Obesity drug therapy   metabolism   MeSH
• Fatty Acids, Omega-3 administration & dosage   pharmacology   MeSH
• Pioglitazone pharmacology   MeSH
• Thiazolidinediones administration & dosage   pharmacology   MeSH
• Triglycerides metabolism   MeSH
• Adipocytes drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hypoglycemic Agents MeSH
• Fatty Acids MeSH
• Fatty Acids, Omega-3 MeSH
• Pioglitazone MeSH
• Thiazolidinediones MeSH
• Triglycerides MeSH

Antisteatotic effects of omega-3 fatty acids (Omega-3) in obese rodents seem to vary depending on the lipid form of their administration. Whether these effects could reflect changes in intestinal metabolism is unknown. Here, we compare Omega-3-containing phospholipids (krill oil; ω3PL-H) and triacylglycerols (ω3TG) in terms of their effects on morphology, gene expression and fatty acid (FA) oxidation in the small intestine. Male C57BL/6N mice were fed for 8 weeks with a high-fat diet (HFD) alone or supplemented with 30 mg/g diet of ω3TG or ω3PL-H. Omega-3 index, reflecting the bioavailability of Omega-3, reached 12.5% and 7.5% in the ω3PL-H and ω3TG groups, respectively. Compared to HFD mice, ω3PL-H but not ω3TG animals had lower body weight gain (-40%), mesenteric adipose tissue (-43%), and hepatic lipid content (-64%). The highest number and expression level of regulated intestinal genes was observed in ω3PL-H mice. The expression of FA ω-oxidation genes was enhanced in both Omega-3-supplemented groups, but gene expression within the FA β-oxidation pathway and functional palmitate oxidation in the proximal ileum was significantly increased only in ω3PL-H mice. In conclusion, enhanced intestinal FA oxidation could contribute to the strong antisteatotic effects of Omega-3 when administered as phospholipids to dietary obese mice.

• Keywords
• Omega-3 index, Omega-3 phospholipids, high-fat diet, krill oil, small intestine,
• MeSH
• Diet, High-Fat * MeSH
• Erythrocyte Membrane metabolism   MeSH
• Euphausiacea MeSH
• Phospholipids administration & dosage   MeSH
• Blood Glucose analysis   MeSH
• Fatty Acids metabolism   MeSH
• Lipid Metabolism drug effects   MeSH
• Mice, Obese MeSH
• Oils MeSH
• Fatty Acids, Omega-3 administration & dosage   MeSH
• Oxidation-Reduction MeSH
• Intestines anatomy & histology   MeSH
• Intestinal Mucosa metabolism   MeSH
• Body Weight MeSH
• Triglycerides administration & dosage   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Phospholipids MeSH
• Blood Glucose MeSH
• Fatty Acids MeSH
• Oils MeSH
• Fatty Acids, Omega-3 MeSH
• Triglycerides MeSH