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Endocrinology Vol. 149, No. 7 3592-3597
Copyright © 2008 by The Endocrine Society

Starvation and Triglycerides Reverse the Obesity-Induced Impairment of Insulin Transport at the Blood-Brain Barrier

Akihiko Urayama and William A. Banks

Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center in St. Louis, Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63106

Address all correspondence and requests for reprints to: William A. Banks, M.D., Veterans Affairs Medical Center, 915 North Grand Boulevard, St. Louis, Missouri 63106. E-mail: Bankswa{at}slu.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Insulin in the brain acts as a satiety factor, reduces appetite, and decreases body mass. Altered sensing by brain of insulin may be a leading cause of weight gain and insulin resistance. A decrease in the transport across the blood-brain barrier (BBB) of insulin may induce brain insulin resistance by inducing obesity. We here report that transport of iv administrated insulin across the BBB of obese mice, as measured by multiple-time regression analysis, was significantly lower than that in thin adult mice. The reduction in obese mice was reversed by starvation for 48 h. There were no differences in insulin transport rates across the BBB of obese, thin, or starved obese mice when studied by the brain perfusion model, demonstrating that BBB transport of insulin is modulated by circulating factors. In the brain perfusion study, the triglyceride triolein significantly increased the brain uptake of insulin, an effect opposite to that on leptin transport, in starved obese mice. Thus, circulating triglycerides are one of the systemic modulators for the transport of insulin across the BBB.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INSULIN IN THE systemic circulation crosses the blood-brain barrier (BBB) to exert effects on the central nervous system (CNS) (1). The brain regulates energy balance by modulating feeding behavior and energy expenditure, thereby leading to changes in circulating fat mass. As serum fat mass increases, circulating levels of insulin and leptin increase as well. Similarity of pharmacological actions by insulin and leptin on energy homeostasis has been observed. For example, both insulin and leptin are transported across the BBB by saturable transporters (2, 3) to act in the CNS as anorexigenic factors by stimulating the proopiomelanocortin (POMC) neurons (4, 5) and by inhibiting the agouti-related protein/neuropeptide Y (AgRP/NPY) neurons in the arcuate nucleus (6). Although the insulin and leptin BBB transporters are separate (3), insulin can modify the activity of the leptin BBB transporter (7). Postreceptor signaling by both peptides appears to share the phosphatidylinositol 3-OH kinase (PI3K) pathway, which has been implicated in obesity and insulin resistance (8, 9). Leptin-mediated effects on suppressor of cytokine signaling-3 (SOCS3) via Janus kinase-signal transducer and activator of transcription (Jak-STAT) activation is known to inhibit signal cascades induced by insulin receptors (10, 11). Thus, there are many interactions between insulin and leptin responses in cellular events, BBB interactions, neuronal responses, and behavioral activities. These interactions can be affected by various regulators and events such as neurotransmitters, nutrients, regulatory peptides and proteins, aging, and obesity (12, 13, 14, 15).

A lack of insulin signaling in the CNS leads to increased ingestive behavior and body weight. Intracerebroventricular injections of oligodeoxynucleotide antisense directed against the precursor protein of the insulin receptor decreases the receptor expression in the arcuate nucleus and induces hyperphagia and insulin resistance (16), and mice genetically lacking neuronal insulin receptors show mild insulin resistance, hyperphagia, and diet-dependent obesity (17).

Because the source of brain insulin is essentially from systemic circulation (18), insulin needs to transverse the BBB before exerting its effects in the brain (19). The BBB is the major regulatory interface between the circulation and the CNS and helps to maintain cerebral homeostasis. Circulating insulin is transported across the BBB by a saturable transport system into most brain regions, including the hypothalamus, pons-medulla, hippocampus, striatum, parietal cortex, and frontal cortex, but not usually into the midbrain, thalamus, and occipital cortex in mice (20). BBB transporters adapt to aging, obesity, and diseases related to cerebral and systemic changes. Indeed, several studies have shown that the transport of insulin across the BBB is impaired by short-term fasting, obesity, and aging (21, 22, 23, 24). In addition, a reduction in insulin levels in the extracellular space of the hypothalamus is associated with obesity (25), and the concentration of hypothalamic insulin in genetically obese Zucker (fa/fa) rats is about 30% of that in young normal rats (25). This suggests an impairment in insulin availability to the brain with obesity.

The reduced level of brain insulin in obese mice is likely caused by a defect in insulin transport across the BBB. However, it is unclear what causes this defective transport of insulin. Previous work has shown a role for blood-borne factors such as triglycerides in impairing leptin transport (26). The present study was undertaken to examine the possible effects of obesity and energy restriction on the passage of insulin across the BBB by comparing the uptake of insulin by brain in thin, obese, and starving obese mice. We found that starvation and the triglyceride triolein reversed the impaired transport of obesity. These effects are opposite to those seen on leptin transport across the BBB.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Radioactive labeling
Five micrograms of human insulin (Sigma Chemical Co., St. Louis, MO) were radioactively labeled by the chloramine-T method with 2 mCi [131I]Na (Amersham Pharmacia, Piscataway, NJ) as previously described (27, 28). Radiolabeled insulin was separated from free iodine on a Sephadex G-10 column. Insulin that was inactivated by undergoing three freeze/thaw cycles was also radioactively labeled by the chloramine-T method and purified on a G-10 column. Each agent was freshly prepared on the day of in vivo and in situ tracer experiments. [131I]Insulin had a specific activity of about 55 µCi/µg.

Animals
Male CD-1 mice from our in-house colony were studied at 8–10 wk (thin adult, 33.7 ± 0.4 g) and retired breeders at 56–64 wk (obese, 69.9 ± 2.0 g) of age. The animals were housed in clean cages in the laboratory with free access to food and water and were maintained on a 12-h dark (1800–0600 h), 12-h light (0600–1800 h) cycle in a room with controlled temperature (24 ± 1 C) and humidity (55 ± 5%). To investigate the effect of diet restriction on the uptake of [131I]insulin, obese adult mice were fasted for 48 h before use (starved obese adult, 63.1 ± 1.5 g). Because circulating insulin levels may be chronographically affected by feeding pattern, the measurement of brain influx rates were conducted during a limited time from 1500–1800 h. All studies were approved by the local Animal Care and Use Committee and were performed in a facility approved by Association for Assessment and Accreditation of Laboratory Animal Care.

Intravenous injection study
Mice anesthetized with 40% urethane received an iv injection of [131I]insulin (500,000 cpm) into the jugular vein. At 1–10 min after the injection, blood was obtained from the carotid artery and the whole brain collected immediately and weighed. Serum was obtained from whole blood by centrifugation. To confirm the transport of intact insulin into the brain, insulin inactivated by three freeze/thaw cycles was also studied. The serum time curves were analyzed with the first-order equation [C(t) = C0e–kt], and pharmacokinetic parameters were calculated. The initial concentration (C0) and the elimination constant (k) were determined from y-intercept of the plot and the slope, respectively. The half-life (t1/2), volume of distribution (Vd), and clearance (CL) were estimated as ln2/k, dose/C0, k.Vd., respectively. The area under the curve (AUC0–10) was calculated by integrating the equation from 0–10 min. The brain/serum ratios were fitted with the second-order polynomial function. The regression analyses were conducted with the Prism 4.0 program (GraphPad, Inc., San Diego, CA).

Multiple-time regression analysis
The blood-to-brain unidirectional influx rate (Ki) of [131I]insulin was calculated using multiple-time regression analysis (29). The brain/serum ratios were plotted against exposure time, and Ki and distribution volume (Vi) values were estimated from the following equation:

Formula 1(1)
where Am and Cp(t) are the counts per minute per gram of brain and the counts per minute per microliter of serum at time t, respectively. Ki is the slope for the linear portion of the relation between the brain/serum ratios and respective exposure times. The exposure time was calculated as the area under the serum concentration time curve (the integral part of above equation) divided by the serum concentration at time t. The y-intercept of the line represents Vi, the distribution volume in the brain at t = 0.

Transcardiac brain perfusion
Mice were anesthetized ip with 40% urethane, the heart exposed, both jugulars severed, and the descending thoracic aorta ligated. A 26-gauge butterfly needle was inserted into the left ventricle of the heart, and the perfusate, containing [131I]insulin with or without triolein (3–30 mg/ml), was infused at a rate of 2 ml/min for 1–5 min. This time range was determined based on the time range showing the linear relationships between brain/serum ratios and exposure time in iv injection study. After perfusion, the whole brain was removed and weighed. The level of radioactivity was determined in a {gamma}-counter. Brain/perfusate ratios were calculated by dividing the radioactivity in a gram of brain by the radioactivity in a milliliter of perfusate. [131I]insulin (200,000 cpm/ml) with or without triolein was diluted in prewarmed physiological buffer (7.19 g/liter NaCl, 0.3 g/liter KCl, 0.28 g/liter CaCl2, 2.1 g/liter NaHCO3, 0.16 g/liter KH2PO4, 0.17 g/liter anhydrous MgCl2, 0.99 g/liter D-glucose, and 1% wt/vol BSA). The effect of triglyceride triolein on insulin transport across the BBB was evaluated 5 min after the perfusion. The perfusate was freshly prepared each day.

Preparation of triolein emulsion
Triolein emulsion was prepared as described previously (26). Briefly, oleate and glycerol were mixed vigorously in chloroform and dried under a stream of nitrogen gas. Resulting residues were resuspended in physiological buffer and mechanically homogenized (Kinematica, Lucerne, Switzerland). The mixture was emulsified by freeze/thaw cycles for at least 12 times in liquid nitrogen and water, respectively. The triolein emulsion was stored at –70 C until use within 48 h.

Data analysis
Regression lines were calculated by the least-squares method. Statistical analysis of data was performed by one-way ANOVA followed by Newman-Keuls multiple-comparison test or by two-tailed paired t test for linear regression results with the Prism 4.0 program.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The serum concentration-time profile of [131I]insulin in thin, obese, and starved obese mice was investigated. The body weights among the group were significantly (P < 0.001) different (Table 1Go). Starved obese mice showed significantly (P < 0.01) reduced body weight (90.3% of nonstarved obese mice). The levels of [131I]insulin in serum declined biphasically with time after iv injection in each age group (Fig. 1Go). For first phase from 1–5 min after iv injection, the half-life of [131I]insulin was similar in each group. In contrast, the AUC for serum was elevated in obese mice, but not in starved obese mice, in comparison with thin adults (Table 1Go).


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  		TABLE 1. Distribution phase pharmacokinetic parameters of [131I]insulin after iv injection

 

Figure 1
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  		FIG. 1. Time courses of radioactivity in serum after iv injection of [131I]insulin in thin, obese, and starved obese mice. Mice received [131I]insulin (500,000 cpm) iv and were killed 1, 2, 3, 4, 5, 7.5, and 10 min after the injection. Each time point represents the mean ± SE of two to five determinations.

 
The relation between the brain/serum ratio of [131I]insulin and exposure time is shown in Fig. 2Go. Brain uptake of [131I]insulin in thin adults showed a biphasic increase and reached a plateau by 10 min after iv injection (Fig. 2AGo). Whereas the uptake in obese mice showed a linear increase with time (Fig. 2Go, A and B), the uptake in starved obese mice was biphasic (Fig. 2BGo). Brain uptake of [131I]insulin showed a linear increase from 1–10 min of exposure time in multiple-time regression analysis in each group. This allowed estimations of the Ki value. Insets in Fig. 2Go show the linear portion of each brain uptake-time profile for the calculation of the Ki and the initial volume of distribution (Vi). The Ki value of [131I]insulin in obese mice (0.33 ± 0.04 µl/g·min) was significantly (P < 0.05) lower than that in both thin adult (0.62 ± 0.15 µl/g·min) and in starved obese mice (0.73 ± 0.16 µl/g·min) (Fig. 3Go). These results show that the decrease in insulin transport across the BBB in obese mice was reversed by starvation. In contrast, there was no difference in the Vi value among the groups, and the values in thin, obese, and starved obese mice were 12.3 ± 0.80, 9.24 ± 0.33, and 9.59 ± 0.73 µl/g, respectively (Fig. 3Go).


Figure 2
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  		FIG. 2. Multiple-time regression analysis of [131I]insulin after iv injection in thin and obese mice. A, Brain/serum ratios of [131I]insulin were plotted against respective exposure time in thin (bullet) and obese ({triangleup}) mice. The ratios of inactivated insulin were also shown in thin ({blacktriangleup}) and obese ({circ}) mice. B, Effects of caloric restriction on brain uptake of [131I]insulin was tested in obese ({triangleup}) and starved obese ({blacksquare}) mice. The second-order polynomial function was used for fitting each curve. R2 values for curve fitting to thin, obese in panel A, obese in panel B, and starved obese mice were 0.735, 0.842, 0.504, and 0.659, respectively. Inset shows the linear portion of the plot for the calculation of the Ki and Vi values. Each line was analyzed with equation 1Go in Materials and Methods. The linearity was evaluated with runs test, and the regression line was not statistically nonlinear.

 

Figure 3
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  		FIG. 3. Comparisons of unidirectional influx rates (A) and initial volumes of distribution (B) in the iv injection study. Each column represents the mean ± SE of three to five determinations. *, Significant difference between the columns at P < 0.05.

 
The brain/serum ratios of inactivated [131I]insulin showed flat lines, in thin and obese mice, and the brain influx rates were below the level of detection (Fig. 2AGo). This shows that the biologically inactivated insulin did not cross the BBB. The Vi value of inactivated [131I]insulin in thin adult mice was consistent with the vascular volumes in the literature (30, 31), suggesting that the inactivated insulin remained within the vascular space of the brain during the course of the experiment and that successful measurement of insulin uptake by whole brain tissue was achieved.

To estimate the direct brain uptake of [131I]insulin from cerebral circulation, brain perfusion, which negates the influence of blood-borne factors, was conducted. Brain/perfusate ratios of [131I]insulin in thin, obese, and starved obese mice showed linear increases (Fig. 4AGo), and the resulting Ki and Vi values are shown in Fig. 4Go, B and C, respectively. There were no statistical differences among Ki and Vi values. Ki values in the perfusion study were comparable to respective values in the iv injection study except in nonstarved obese mice.


Figure 4
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  		FIG. 4. A, Multiple-time regression analysis of [131I]insulin in brain perfusion model; B and C, comparisons of unidirectional influx rates (B) and initial volumes of distribution (C) in brain perfusion model. The brain was perfused with prewarmed physiological buffer containing [131I]insulin (200,000 cpm/ml). Results are the mean ± SE of three determinations.

 
Effects of the triglyceride triolein on brain uptake of [131I]insulin in obese mice was also investigated in the brain perfusion model. The uptake of [131I]insulin by brain was increased by co-perfusion of triolein in a dose-dependent manner (Fig. 5Go). At the concentration of 30 mg/ml triolein, there was a significant increase of [131I]insulin uptake by brain compared with both nonstarved and starved obese mice (Fig. 5Go).


Figure 5
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  		FIG. 5. Effects of triolein on brain uptake of [131I]insulin in obese mice in the brain perfusion model. The brain was perfused with prewarmed physiological buffer containing [131I]insulin (200,000 cpm/ml) with triolein (0–30 mg/ml). Each column represents the mean ± SE of five to 10 determinations. Asterisks show a significant difference from the nonstarved obese mice: *, P < 0.05; ***, P < 0.001. Daggers show a significant difference from starved obese mice without triolein co-perfusion: {dagger}{dagger}, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Brain insulin is a neuromodulator involved in the control of energy balance, and the source of cerebral insulin is from the circulation. Insulin within the brain acts as a satiety factor; it decreases serum insulin levels, raises serum glucose levels, reduces appetite, and decreases body mass (1, 17, 32, 33). Insulin also has effects on brain development and on cognition (34, 35). Reduced sensing of insulin is proposed as a leading cause of weight gain and insulin resistance (16, 17). Thus, the alteration in BBB transport of insulin is of importance in obesity. Because the transport of insulin across the BBB is impaired by aging (24), it is impossible to discriminate between the effects mediated by obesity itself and by aging itself. However, comparing insulin transport in lean young mice and aged obese mice tracks physiological and/or pathophysiological development of obesity and insulin resistance with aging.

In the present study, we have investigated insulin transport across the BBB in obesity and starvation. Serum levels of iv administrated radioactive insulin during the early phase of clearance were higher in obese mice than that in thin mice, but the levels were reduced when obese mice were starved for 48 h (Fig. 1Go and Table 1Go). Brain uptake of insulin in obese mice was constantly lower than that in thin mice, and the reduction in the unidirectional influx rate (Ki) in obese mice was significant when compared with that in thin adults (Figs. 2Go and 3Go). Consistent with this decreased transport across the BBB, the obese Zucker rat has lower levels of insulin in the brain (23). It has also been demonstrated that transport across the BBB of insulin (22, 36), like that of leptin (37), is reduced with obesity, and relative levels of insulin in the brain and the periphery are decreased in obesity (22, 23, 38). Thus, brain insulin resistance in obesity involves decreased transport of insulin from the circulation.

The brain uptake of insulin in obese and starved obese mice was investigated (Figs. 2Go and 3Go) after iv injection. Starved obese mice showed a biphasic increase of insulin uptake in contrast to the linearity in nonstarved obese mice, and there was a significant difference in resulting Ki values. The Ki values in starved obese mice increased significantly and were similar to the levels in thin adult mice, suggesting the reduced transport in obesity is acquired, but reversible. These results are consistent with the literature showing that chronic restriction in calories results in restoration of insulin sensitivity (39).

Insulin inactivated by freeze/thaw cycles was not taken up by brain (Fig. 2Go). This confirms that measured Ki values for intact insulin represent physiological rates of insulin crossing the BBB in thin adult and obese mice, respectively. It has been reported that deamidation of insulin occurs in the frozen state (40). Therefore, this structural change may be critical for the recognition of insulin by its BBB transporter, and the amide residue of intact insulin is key for its transport.

Whereas the activity of the insulin transport system was apparently down-regulated in obese mice as seen in the iv injection study (Figs. 2Go and 3Go), there were no differences in transport rates measured in the brain perfusion model (Fig. 4Go). This suggests that the altered transport of insulin by the BBB is mediated by circulating factors and is immediately reversible. One such factor could be serum insulin itself, because it is higher in obesity. Triglycerides are also known to respond biphasically to energy deprivation, decreasing with short-term fasting, increasing with starvation, and tending to be elevated with obesity (26).

In the brain perfusion study, the triglyceride triolein significantly increased the brain uptake of insulin in starved obese mice in a dose-dependent manner (Fig. 5Go), suggesting circulating triglycerides are one of the systemic modulators for the transport of insulin across the BBB. The biphasic response of triglyceride levels in serum (26) also explains the reduced insulin transport across the BBB induced by short-term fasting (21), reflecting the decreased levels of triglycerides in serum.

Physiological levels of triglycerides in serum are generally less than 3 mg/ml. However, we did not find an effect of physiological levels of triglycerides on insulin transport during the very short brain perfusion time of 5 min. Higher levels of triglycerides did affect insulin transport during brain perfusion. It may be that longer perfusion times would allow lower concentrations of triglycerides to affect insulin transport. These results support the idea that elevated triglycerides may at least in part be responsible for the increase in insulin transport seen during starvation.

An important aspect of triglycerides on BBB transport is the difference in the regulation in insulin and leptin transport. Both insulin and leptin transport across the BBB are reduced in obesity. However, manipulation of triglyceride levels with diet or starvation in normal or obese mice has an inverse effect on leptin transport (26). That is, leptin transport across the BBB increased with short-term fasting but decreased with starvation and with administration of triolein. In contrast, insulin transport is decreased by short-term fasting (21) but increased by starvation (Fig. 3Go) and by triolein (Fig. 5Go). Additionally, brain perfusion only partially reverses impaired BBB transport of leptin in obese animals (26), whereas it totally reversed the impaired transport of insulin (Fig. 4Go). Therefore, the obesity-related impairment of leptin transport is not totally accounted for by the immediate effects of circulating substances.

Whereas there are many crossover effects of insulin and leptin in the CNS such as the coordinate effects on the proopiomelanocortin and/or agouti-related protein/neuropeptide Y neurons in the arcuate nucleus, cellular signal transductions mediated by the phospholipase C, phosphatidylinositol 3-OH kinase, and the mitogen-activated protein kinase cascades (41, 42, 43), the current results show that their transport across the BBB can be modulated differently in obesity and by circulating triglycerides.

Our obesity model is confounded by age. With this limitation, we cannot solely attribute the decrease in insulin transport in obese mice to an age effect or to obesity. However, we found the decreased transport of insulin in obese mice was immediately reversible when mice were in the starved condition, suggesting that both younger and obese mice certainly retain a similar capability to transport insulin into the brain. Thus, there is no change in the insulin transport property at the BBB; in turn, the apparent difference in the transport may be attributed to peripheral factors that may be induced by both obesity and aging.

In conclusion, we show the effects of obesity and starvation on insulin transport across the BBB are mediated by serum factors. One such factor is possibly triglycerides, which increase the transport of insulin across the BBB.


   Acknowledgments
 
We thank Ms. Miho Urayama for her excellent suggestions on this work.


   Footnotes
 
This work was supported by VA Merit Review Grants R01NS41863 and R21DA019396 (to W.A.B.).

Current Address for A.U.: The Laboratory of Protein Misfolding Disorders, Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555-1045.

Disclosure Statement: A.U. and W.A.B. have nothing to declare.

First Published Online April 10, 2008

Abbreviations: AUC, Area under the curve; BBB, blood-brain barrier; CNS, central nervous system; Ki, influx rate; Vi, distribution volume.

Received January 3, 2008.

Accepted for publication April 1, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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