Glucose and Insulin Increase the Transport of Leptin through the Blood-Brain Barrier in Normal Mice but Not in Streptozotocin-Diabetic Mice

Abstract

Since fasting is one of the few factors found to change the rate of entry of leptin into brain, we used multiple-time regression analysis to study the effects of pretreatment with glucose or insulin on leptin transport across the blood-brain barrier (BBB). Two hours after intraperitoneal injection of glucose (3 g/kg), there was a statistically significant increase in the entry rate (K_i) of leptin in fasted (from 4.91 ± 0.70 × 10^–4 ml/g min to 9.03 ± 1.00 × 10^–4 ml/g min) but not (p = 0.15) in nonfasted normal (from 4.90 ± 1.21 × 10^–4 ml/g min to 6.42 ± 1.79 × 10^–4 ml/g min) or fasted streptozotocin (STZ)-treated diabetic mice (from 4.043 ± 0.959 × 10^–4 ml/g min to 5.395 ± 1.355 × 10^–4 ml/g min). Insulin (10 U/kg) increased leptin influx in fasted (from 4.77 ± 0.26 × 10^–4 ml/g min to 10.6 ± 0.15 × 10^–4 ml/g min at 0.5 h) and nonfasted (from 4.64 ± 0.75 × 10^–4 ml/g min to 7.46 ± 1.48 × 10^–4 ml/g min at 0.5 h) normal mice, but not in STZ-diabetic mice deficient in insulin (and leptin), even though basal concentrations of glucose were similarly increased in the nonfasted normal and STZ-treated mice. Moreover, the basal rate of leptin influx was the same in overnight fasted normal mice, nonfasted normal mice and STZ-diabetic mice. The results indicate that glucose and insulin can increase leptin transport, but they probably are not the principal factors responsible for the regulatory effect of the BBB on leptin entry into the brain.

Triglycerides Induce Leptin Resistance at the Blood-Brain Barrier

“…Triglycerides could produce their effect on leptin transport by binding leptin in the circulation or by acting directly on the leptin transporter. Other BBB transporters are known to be regulated by uncompetitive and noncompetitive mechanisms (38,39), and leptin transport is altered by ␣ 1 -adrenergic agonists, glucose, and insulin (40,41). It may be that the leptin transporter possesses a regulatory site controlled by triglycerides.…”

Central leptin insufficiency syndrome: An interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions

“…These include increased binding of leptin to CRP and modulation of blood to brain transport by various metabolic variables in the peripheral circulation [8,11,14,32,53,82,83,85,112]. In sum, these two endogenous defensive mechanisms are pressed into high gear to reduce leptin levels in the brain with a common goal of averting undereating and starvation, and initiating those additional hypothalamic mechanisms that promote storage of excess energy as fat, without jeopardizing the daily feeding pattern (see below).…”

“…On the other hand, as proposed earlier [41,42,72,76], the cumulative body of scientific evidence fits better with the alternate concept of hypothalamic leptin insufficiency in causation of obesity and metabolic syndrome. The major tenet of this postulation is that BBB restricts the blood to brain entry of leptin in response to hyperleptinemia consisting of heightened rhythmic leptin drive induced by energy enriched diets and intrinsic daily secretion pattern, and attendant varied blood-borne factors [6,8,[11][12][13][14]27,29,32,53,73,[82][83][84]109,111,118,141, Fig. 2].…”

“…A further crucial issue here, and one that is usually overlooked is the fact that leptin permeability across the BBB, a first step towards development of leptin insufficiency, is itself subject to modulation by a spectrum of endogenous factors. In addition to adiposity, intrinsic circadian rhythms governing ingestive behavior, daily mealtimes, afferent ultradian rhythms in hormonal feedback signaling critical in hypothalamic integration of the daily feeding pattern, wide ranging blood borne neuroactive metabolic variables and aging itself can affect leptin transport from blood to brain [8][9][10][11][12][13][14]29,73,[82][83][84][85]98,[110][111][112]. Furthermore, since leptin exerts pleiotropic effects in the brain, BBBinduced suboptimal or defective pattern of leptin signaling at extrahypothalamic targets, either directly or secondarily due to breakdown in hypothalamic integration of energy homeostasis, can potentially contribute to a spectrum of neural disorders.…”

“…Blood-borne hormones and circulating metabolic variables also independently modulate the BBB transport system to quantitatively affect leptin availability at CNS sites. For example, α-adrenergic agonist epinephrine, insulin and glucose enhance and triglycerides inhibit the transport of leptin across the BBB [8][9][10][11][12][13][14]47,83,85,91,98,138].…”