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Leptin and Sleep

BL

Sleep apnea

is a condition in which a sleeping individual’s breathing stops or becomes shallow.

Obstructive sleep apnea arises from the collapse of the walls of soft tissue in the airways.   Individuals with low muscle-tone and soft tissue around the airway (e.g., because of obesity) and structural features that give rise to a narrowed airway are at high risk for obstructive sleep apnea.

Central, or Cheyne-Stokes respiration,sleep apnea arises from lack of brain stem response to aveolar elevation in carbon dioxide.   The communication of oxygen sensors in the  carotid body  of the carotid artery may also be impaired.   The carotid body also responds to decreases in pH, increases in carbon dioxide, and temperature drops.  Agents that block respiration also stimulate the glossopharyngeal nerve (CN IX) that connects the carotid body to the  Solitary Nucleus.  

Obesity Hypoventilation Syndrome

Obese individuals tend to have increased levels of fat cell derived leptin in their circulation.  Carotid body signals to the brain stem is blunted in obese individuals.   OHS is thought to arise from central resistance to leptin.  OHS is particularly a problem during sleep.

How is leptin involved?

A multi-center study was led by Vsevolod Polotsky of John Hopkins Medical Institute.  The goal was to investigate the central nervous system role in obesity related  hypoventilation and obstructive sleep apnea.  These symptoms arise from  defects in respiratory pump and upper airway neural control.   An  ob/ob mouse model was chosen for this study.  These chronically obese mice lack both copies of the gene for leptin.   These mice have impaired ventilatory control and inspiratory flow limitation during sleep, both of which are reversed by  leptin.

Leptin1
A cartoon from Caymen Biochemical showing  the interplay between leptin and ghrelin in appetite control and metabolism. Right inset shows an Ob/Ob mouse lacking both copies of the leptin gene and its wild type counterpart.

Could leptin be acting on the hypothalamus or the brain stem?  In order to differentiate between the two, leptin was injected into ventricles in close proximity to these two regions.

Leptin3
The authors injected  leptin (10 μg/2 μL) or vehicle to the lateral (n = 14) versus fourth ventricle (n = 11) of ob/ob mice followed by polysomnographic recording.  The image on the right shows the positions of the ventricles in the rat brain.  The image on the right

The work of Yao and coworkers is available free online.  Let’s look at two key figures in this report.

Leptin decreases episodes of hypoxia

Figure 4 shows the influence of intracerebroventricular administration of leptin (10 μg/2 μL in 5 mM Tris HCl) or vehicle (2 μL of 5 mM Tris HCl) on the oxygen desaturation index (ODI).  Thris HCl is a buffer used to control the pH of solutions.

Leptin4
From Figure 4, Yao (2016). Injection of leptin in the lateral, but not 4th, ventricle decreased the number of episodes of low oxygen saturation of hemoglobin. REM, rapid eye movement sleep.  NREM, non-rapid eye movement sleep.

While there was some hint of an influence of 4th ventricle administration of leptin, the statistical testing indicated that this difference could be due to random variation.  The same testing revealed that we can be 95% certain that the decrease in number of episodes of low ODI was truly due to the leptin injected into the lateral ventricle.

 How leptin might be working

Leptin is a peptide hormone that binds to receptors in the cell membrane.  Leptin binding causes its receptor to dimerize.  Dimerization triggers the activation of “kinase” enzyme.  Kinases place phosphate groups on amino acids such as tyrosine (Y).

  • When STAT3 is phosphorylated, it forms a dimer.
  • The STAT3 dimer translocates to the nucleus and causes genes to be transcribed into messenger RNA.
  • The messenger RNA leaves the nucleus and tells the ribosomes to make protein.
  • In the DMH of the hypothalamus, these proteins might be  prolactin-releasing peptide, cocaine- and amphetamine-regulated transcript, and galanin
Leptin2
From Figure 5, Yao (2016) with adaptations. Left a cartoon of Leptin binding to its receptor and causing the phosphorylation of transcription factor STAT3.  Right, immunostaining with antibodies against phosphorylation STAT3.  Regions positive for phosphorylated STAT3 appear to be brown above the background.

 

Brain regions containing phosphorylated STAT3 activated by leptin

  •  Numerous positive pSTAT3 nuclei were noted in  arcuate nucleus and dorsomedial hypothalamus(5A)
  • In the medulla, the most abundant pSTAT3 positive nuclei were located in the nucleus of the solitary tract NTS, (5B).
  • No positive staining was detected in the hypoglossal nucleus (XII)..

 

Aspects of Yao (2016) not covered in this blog

  • Use of an attenuated rabies virus injected into the diaphragm that showed respiratory motor neurons innervating the diaphragm projected to the NTS, but not to the hypothalamus or any other areas in the forebrain.
  • A representative polysomnography that includes (1) respiratory flow, (2) EEG, (3) EMG, (4) flow, (5) effort, and (6) oxygen saturation.

 

Yao Q, Pho H, Kirkness J, Ladenheim EE, Bi S, Moran TH, Fuller DD, Schwartz AR, Polotsky VY.(2016) Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep. Sleep. 39(5):1097-106. Free Paper

Published by BL

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