Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance

Abstract

Objective: Resistance at the brain receptors for leptin and insulin has been associated with increased feeding, obesity and cognitive impairments. The causal agent for central resistance is unknown but could be derived from the blood. Here we postulate whether hypertriglyceridemia, the major dyslipidemia of the metabolic syndrome, could underlie central leptin and insulin resistance.

Design: We used radioactively labeled triglycerides to measure blood-brain barrier (BBB) penetration, western blots to measure receptor activation, and feeding and cognitive tests to assess behavioral endpoints.

Results: Human CSF was determined to contain triglycerides, a finding previously unclear. The radioactive triglyceride triolein readily crossed the BBB and centrally administered triolein and peripherally administered lipids induced in vivo leptin and/or insulin resistance at hypothalamic receptors. Central triolein blocked the satiety effect of centrally administered leptin. Decreasing serum triglycerides with gemfibrozil improved both learning and memory inversely proportionate to triglyceride levels.

Conclusions: Triglycerides cross the blood-brain barrier rapidly, are found in human cerebrospinal fluid, and induce central leptin and insulin receptor resistance, decreasing satiety and cognition.

Figure 1

Triglycerides are present in human CSF and cross the murine blood–brain barrier. (a) Triglycerides are detected in human lumbar cerebrospinal fluid drawn from a convenience sample (n=39). (b) The radioactively labeled triglyceride triolein crossed the mouse blood–brain barrier to accumulate in brain (n shown in parentheses).

Figure 2

Activation of the leptin or insulin receptor is inhibited by the triglyceride triolein. (a) Leptin given by intracerebroventricular (ICV) injection activates receptor signaling in a dose-dependent manner. (b) Co-administered triolein prevents leptin from activating its receptor. (c) Insulin given by ICV injection activates receptor signaling in a dose-dependent manner. (d) Co-administration of triolein prevents insulin from activating its receptor. Number in parentheses represents the n; *P<0.05; **P<0.01

Figure 3

Effects of the triglyceride triolein on regional brain uptake of ICV administered leptin. Triolein increased leptin uptake by whole brain, and the regions of the striatum, hypothalamus, occipital cortex, cerebellum and midbrain. N=10 per group; *P<0.05; **P<0.01.

Figure 4

Co-Administration of the triglyceride triolein blocks the anorectic effect of leptin given by intracerebroventricular (ICV) injection. (a) Feeding results for 0–24 after ICV administrations (b) Feeding results for 4–24 h after ICV administrations. N=10 per group. V–-V: only vehicle was injected; V–L: leptin injected without triolein; T-–L: triolein and leptin co-injected. *P<0.05.

Figure 5

Lowering plasma triglycerides with gemfibrozil (gem) improves cognition. (a) Triglyceride levels correlate with acquisition (learning). (b) Triglyceride levels correlate with retention (memory). Con, =control; Gem, gemfibrozil-treated.

Figure 6

Peripheral triglycerides cross the BBB to induce leptin resistance. (a) Samples of western blots after IP no fat milk and ICV lactated Ringers’s solution (NC, n=9), IP no fat milk and ICV leptin (NL, n=8), IP whole fat milk and ICV lactated Ringer’s solution (WC, n=10), or IP whole fat milk and ICV leptin (WL, n=10). (b) ICV leptin induced less STAT phosphorylation in mice treated with IP whole milk than in mice treated with IP no fat milk. (c) Percent of IP dose of radioactive triolein co-administered with whole fat milk that was taken up by brain regions or serum; n=5 per group. *P<0.05; ***P<0.005; ****P<0.001.