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Leptin and the Blood‐Brain Barrier: Curiosities and Controversies

William A. Banks

10.1002/cphy.c200017

Source: Volume 11, Issue 4, October 2021

Published online: September 2021

Full Article on Wiley Online Library



Abstract

Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood‐brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:2351‐2369, 2021.

Figure 1. Figure 1. Relation of mean levels of serum leptin and BMI from six classic studies. Data is fitted to an exponential growth curve: Serum leptin = Y0k(BMI), where Y = 0.0195 and k = 0.238 (n = 10, r2 = 0.847). Reused, with permission, from Arnulf I, et al., 2006 4; Caro JF, et al., 1996 32; Koistinen HA, et al., 1998 85; Mantzoros C, et al., 1997 100; Schwartz MW, et al., 1996 143; Wiedenhoft A, et al., 1999 163.
Figure 2. Figure 2. Classic negative feedback loops. (A) The classic negative feedback loop is illustrated. Effector hormone released from the effector tissue stimulates the target tissue to secrete the controlled substance. The controlled substance suppresses release of the effector hormone. Thus, the system is self‐regulated at a steady‐state value. (B) The negative feedback controlling thyroid hormone levels. (C) The negative feedback loop controlling calcium levels. (D) The negative feedback loop controlling glucose levels. (E) The leptin‐adipose tissue feedback loop as an adipostat. (F) The leptin negative feedback loop with two points of resistance in series: the BBB and the arcuate nucleus.
Figure 3. Figure 3. Blood and CSF leptin levels from six classic leptin studies. (A) Relation of mean leptin levels for CSF vs. blood fitted to a one‐site hyperbolic model. These six studies evaluated levels in several categories besides obese and lean, including children, anorexia nervosa, and narcolepsy. The Kd of the hyperbola (the x value at which 50% of the maximum Y value is achieved) is shown by the vertical dashed line and is 3.74 ng/mL. (B) The CSF/serum ratios from these six studies plotted against their respective values for blood leptin levels. The horizontal dashed line is at the ratio of 0.005 (or 0.5%), the approximate brain/serum ratio for albumin in young healthy individuals. Reused, with permission, from Arnulf I, et al., 2006 4; Caro JF, et al., 1996 32; Koistinen HA, et al., 1998 85; Mantzoros C, et al., 1997 100; Schwartz MW, et al., 1996 143; Wiedenhoft A, et al., 1999 163.
Figure 4. Figure 4. Comparison of brain vs. blood and CSF vs. blood relations. CSF data from the six studies of Figure 3 plotted with a perfusion study done in mice correlating vascular leptin levels with brain levels of leptin. Both fit a hyperbolic pattern although the curve for CSF is shifted to the left, indicating saturation at a lower vascular level of leptin. Reused, with permission, from Banks WA, et al., 2000 11.
Figure 5. Figure 5. A strong correlation exists between the mean CSF levels of the six classic studies and BMI (r2 = 0.685, P = 0.003). Modeling demonstrates that an elevation in CSF levels of leptin is consistent with resistance at the leptin receptor. This is both because CSF is proximal to the receptor and so reflects resistance at the receptor and also because resistance at only the BBB would result in normal CSF leptin levels (but elevated blood and decreased CSF/serum ratios of leptin).
Figure 6. Figure 6. Modeling of one vs. two sites of impairment. Although both are nonlinear, the two‐site model is obviously much more so. This explains the apparent linearity of CSF leptin levels vs. BMI, which reflects resistance at one site vs. the hyperbolic increase in serum leptin levels at the same range of BMI's as serum reflects resistance at two sites: the BBB and the CNS receptor.
Figure 7. Figure 7. Comparison of leptin vascular levels and CSF/serum levels achieved by suprapharmacological leptin doses. The left hand portion of the graph shows the values measured in the six classic studies plus the controls from the 1 mg/kg study. All values in the left‐hand portion have vascular levels less than 50 ng/mL (the vertical dashed line) and CSF/serum ratios greater than 0.005 (or 0.5%). The right‐hand portion of the figure shows values in animals treated with 1 or 2.5 mg/kg. Blood values are typically 10 to 30 times greater than those seen in obesity, and CSF/serum rations less than 0.005. At the suprapharmacological levels, entry into the CNS is likely by way of the nonsaturable extracellular pathways as the transporters across the barriers are saturated.
Figure 8. Figure 8. Substances and conditions that modulate the transport of leptin at the BBB. Conditions that increase leptin transport across the BBB are shown in the green trapezoid, and substances in the green rectangle. Conditions that inhibit leptin transport across the BBB are shown in the red trapezoid. Triglycerides and leptin inhibit BBB transport of leptin and also cross the BBB to induce resistance at the leptin receptor in the arcuate nucleus.


Figure 1. Relation of mean levels of serum leptin and BMI from six classic studies. Data is fitted to an exponential growth curve: Serum leptin = Y0k(BMI), where Y = 0.0195 and k = 0.238 (n = 10, r2 = 0.847). Reused, with permission, from Arnulf I, et al., 2006 4; Caro JF, et al., 1996 32; Koistinen HA, et al., 1998 85; Mantzoros C, et al., 1997 100; Schwartz MW, et al., 1996 143; Wiedenhoft A, et al., 1999 163.


Figure 2. Classic negative feedback loops. (A) The classic negative feedback loop is illustrated. Effector hormone released from the effector tissue stimulates the target tissue to secrete the controlled substance. The controlled substance suppresses release of the effector hormone. Thus, the system is self‐regulated at a steady‐state value. (B) The negative feedback controlling thyroid hormone levels. (C) The negative feedback loop controlling calcium levels. (D) The negative feedback loop controlling glucose levels. (E) The leptin‐adipose tissue feedback loop as an adipostat. (F) The leptin negative feedback loop with two points of resistance in series: the BBB and the arcuate nucleus.


Figure 3. Blood and CSF leptin levels from six classic leptin studies. (A) Relation of mean leptin levels for CSF vs. blood fitted to a one‐site hyperbolic model. These six studies evaluated levels in several categories besides obese and lean, including children, anorexia nervosa, and narcolepsy. The Kd of the hyperbola (the x value at which 50% of the maximum Y value is achieved) is shown by the vertical dashed line and is 3.74 ng/mL. (B) The CSF/serum ratios from these six studies plotted against their respective values for blood leptin levels. The horizontal dashed line is at the ratio of 0.005 (or 0.5%), the approximate brain/serum ratio for albumin in young healthy individuals. Reused, with permission, from Arnulf I, et al., 2006 4; Caro JF, et al., 1996 32; Koistinen HA, et al., 1998 85; Mantzoros C, et al., 1997 100; Schwartz MW, et al., 1996 143; Wiedenhoft A, et al., 1999 163.


Figure 4. Comparison of brain vs. blood and CSF vs. blood relations. CSF data from the six studies of Figure 3 plotted with a perfusion study done in mice correlating vascular leptin levels with brain levels of leptin. Both fit a hyperbolic pattern although the curve for CSF is shifted to the left, indicating saturation at a lower vascular level of leptin. Reused, with permission, from Banks WA, et al., 2000 11.


Figure 5. A strong correlation exists between the mean CSF levels of the six classic studies and BMI (r2 = 0.685, P = 0.003). Modeling demonstrates that an elevation in CSF levels of leptin is consistent with resistance at the leptin receptor. This is both because CSF is proximal to the receptor and so reflects resistance at the receptor and also because resistance at only the BBB would result in normal CSF leptin levels (but elevated blood and decreased CSF/serum ratios of leptin).


Figure 6. Modeling of one vs. two sites of impairment. Although both are nonlinear, the two‐site model is obviously much more so. This explains the apparent linearity of CSF leptin levels vs. BMI, which reflects resistance at one site vs. the hyperbolic increase in serum leptin levels at the same range of BMI's as serum reflects resistance at two sites: the BBB and the CNS receptor.


Figure 7. Comparison of leptin vascular levels and CSF/serum levels achieved by suprapharmacological leptin doses. The left hand portion of the graph shows the values measured in the six classic studies plus the controls from the 1 mg/kg study. All values in the left‐hand portion have vascular levels less than 50 ng/mL (the vertical dashed line) and CSF/serum ratios greater than 0.005 (or 0.5%). The right‐hand portion of the figure shows values in animals treated with 1 or 2.5 mg/kg. Blood values are typically 10 to 30 times greater than those seen in obesity, and CSF/serum rations less than 0.005. At the suprapharmacological levels, entry into the CNS is likely by way of the nonsaturable extracellular pathways as the transporters across the barriers are saturated.


Figure 8. Substances and conditions that modulate the transport of leptin at the BBB. Conditions that increase leptin transport across the BBB are shown in the green trapezoid, and substances in the green rectangle. Conditions that inhibit leptin transport across the BBB are shown in the red trapezoid. Triglycerides and leptin inhibit BBB transport of leptin and also cross the BBB to induce resistance at the leptin receptor in the arcuate nucleus.
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Article Title: Leptin and the Blood‐Brain Barrier: Curiosities and Controversies
 

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William A. Banks. Leptin and the Blood‐Brain Barrier: Curiosities and Controversies. Compr Physiol 2021, 11: 2351-2369. doi: 10.1002/cphy.c200017