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

• Published in: International Journal of Obesity Vol. 42; no. 3; pp. 391 - 397
• Main Authors: Banks, W A, Farr, S A, Salameh, T S, Niehoff, M L, Rhea, E M, Morley, J E, Hanson, A J, Hansen, K M, Craft, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2018; Nature Publishing Group
• Subjects: 631/378/1488/1562; 631/443/319/1557; Aged; Animals; Antigens, CD - metabolism; Blood-brain barrier; Blood-Brain Barrier - metabolism; Care and treatment; Cerebrospinal fluid; Cognition; Cognition - drug effects; Cognitive ability; Development and progression; Dyslipidemia; Dyslipidemias; Epidemiology; Feeding; Female; Gemfibrozil; Gemfibrozil - pharmacology; Health aspects; Health Promotion and Disease Prevention; Human behavior; Humans; Hypertriglyceridemia; Hypothalamus; In vivo methods and tests; Insulin; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Learning; Leptin; Leptin - metabolism; Leptin - pharmacology; Lipids; Male; Maze Learning - drug effects; Medicine; Medicine & Public Health; Memory; Metabolic Diseases; Metabolic disorders; Metabolic syndrome; Original; original-article; Physiological aspects; Public Health; Receptor mechanisms; Receptor, Insulin - metabolism; Receptors; Satiety; Satiety Response - drug effects; Triglycerides; Triglycerides - blood; Triglycerides - cerebrospinal fluid; Triglycerides - metabolism; Triolein; Triolein - metabolism; Triolein - pharmacology; Western blotting
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2017.231

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.