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Obesity is associated with leptin resistance caused by impaired leptin transport across the BBB, defects in leptin-receptor signaling, and blockades in downstream neuronal circuitries. The inability of obese mice to respond to peripherally administered leptin while responding to centrally administered leptin is likely caused by a defect in leptin transport across the BBB. It is unclear what causes defective transport of leptin in either obesity or starvation. Because serum triglycerides are elevated in both starvation and obesity, we postulated that triglycerides inhibit leptin transport across the BBB. Here, we showed that starvation-induced inhibition of leptin transport was caused by a circulating factor; that the fat component of milk which is 98% triglycerides ; as well as specific triglycerides could induce inhibition of leptin transport across the BBB in vivo, in situ, and in vitro; that the FFAs comprising those triglycerides were ineffectual; that manipulation of triglyceride levels with diet or fasting in normal or obese mice had an inverse effect on leptin transport; and that reduction of triglycerides by pharmacological intervention reversed the impairment in leptin transport. Taken together, these findings show that triglycerides directly inhibit the transport of leptin across the BBB and so could be a major cause of leptin resistance at the BBB. We fasted mice for 48 h to determine whether starvation impairs the transport of intravenously administered I-Lep. We confirmed that short-term fasting decreased serum triglyceride levels, whereas 48 h of fasting starvation ; increased them. The level of reduction in the brain uptake of intravenous administered I-Lep was almost identical to the results found by others 20 ; . That group further showed that longer fasts progressively impaired leptin transport across the BBB to the point of total inhibition after 5 days of starvation. This inhibition of leptin transport and the accompanying decrease in levels of leptin in the blood 21 ; are likely adaptive because they would reduce the anorectic signal in starvation. In contrast to intravenous injection, brain perfusion, because atarax wiki. 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