Fish oil supplementation alleviates metabolic and anxiodepressive effects of diet-induced obesity and associated changes in brain lipid composition in mice.

OBJECTIVE: Obesity significantly elevates the odds of developing mood disorders. Chronic consumption of a saturated high-fat diet (HFD) elicits anxiodepressive behavior in a manner linked to metabolic dysfunction and neuroinflammation in mice. Dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) can improve both metabolic and mood impairments by relieving inflammation. Despite these findings, the effects of n-3 PUFA supplementation on energy homeostasis, anxiodepressive behavior, brain lipid composition, and gliosis in the diet-induced obese state are unclear. METHODS: Male C57Bl/6J mice were fed a saturated high-fat diet (HFD) or chow for 20 weeks. During the last 5 weeks mice received daily gavage ("supplementation") of fish oil (FO) enriched with equal amounts of docosahexaenoic (DHA) and eicosapentaenoic acid (EPA) or control corn oil. Food intake and body weight were measured throughout while additional metabolic parameters and anxiety- and despair-like behavior (elevated-plus maze, light-dark box, and forced swim tasks) were evaluated during the final week of supplementation. Forebrain lipid composition and markers of microglia activation and astrogliosis were assessed by gas chromatography-mass spectrometry and real-time PCR, respectively. RESULTS: Five weeks of FO supplementation corrected glucose intolerance and attenuated hyperphagia in HFD-induced obese mice without affecting adipose mass. FO supplementation also defended against the anxiogenic and depressive-like effects of HFD. Brain lipids, particularly anti-inflammatory PUFA, were diminished by HFD, whereas FO restored levels beyond control values. Gene expression markers of brain reactive gliosis were supressed by FO. CONCLUSIONS: Supplementing a saturated HFD with FO rich in EPA and DHA corrects glucose intolerance, inhibits food intake, suppresses anxiodepressive behaviors, enhances anti-inflammatory brain lipids, and dampens indices of brain gliosis in obese mice. Together, these findings support increasing dietary n-3 PUFA for the treatment of metabolic and mood disturbances associated with excess fat intake and obesity.

Triiodothyronine increases myocardial function and pyruvate entry into the citric acid cycle after reperfusion in a model of infant cardiopulmonary bypass.

Triiodothyronine (T3) supplementation improves clinical outcomes in infants after cardiac surgery using cardiopulmonary bypass by unknown mechanisms. We utilized a translational model of infant cardiopulmonary bypass to test the hypothesis that T3 modulates pyruvate entry into the citric acid cycle (CAC), thereby providing the energy support for improved cardiac function after ischemia-reperfusion (I/R). Neonatal piglets received intracoronary [2-(13)Carbon((13)C)]pyruvate for 40 min (8 mM) during control aerobic conditions (control) or immediately after reperfusion (I/R) from global hypothermic ischemia. A third group (I/R-Tr) received T3 (1.2 µg/kg) during reperfusion. We assessed absolute CAC intermediate levels and flux parameters into the CAC through oxidative pyruvate decarboxylation (PDC) and anaplerotic carboxylation (PC) using [2-(13)C]pyruvate and isotopomer analysis by gas and liquid chromatography-mass spectrometry and (13)C-nuclear magnetic resonance spectroscopy. When compared with I/R, T3 (group I/R-Tr) increased cardiac power and oxygen consumption after I/R while elevating flux of both PDC and PC (∼4-fold). Although neither I/R nor I/R-Tr modified absolute CAC levels, T3 inhibited I/R-induced reductions in their molar percent enrichment. Furthermore, (13)C-labeling of CAC intermediates suggests that T3 may decrease entry of unlabeled carbons at the level of oxaloacetate through anaplerosis or exchange reaction with asparate. T3 markedly enhances PC and PDC fluxes, thereby providing potential substrate for elevated cardiac function after reperfusion. This T3-induced increase in pyruvate fluxes occurs with preservation of the CAC intermediate pool. Our labeling data raise the possibility that T3 reduces reliance on amino acids for anaplerosis after reperfusion.