Brain Leptin Resistance in Human Obesity Revisited
Brain Leptin Resistance in Human Obesity Revisited
Abstract & Commentary
By Helen Sohn, MD, Assistant Professor of Surgery, Department of Surgery, USC. Dr. Sohn reports no financial relationship relevant to this field of study.
Synopsis: This study indicates that it is very difficult to explain human obesity on the basis of central nervous system "leptin resistance," in that leptin is released in the brain, and at a higher level in the obese, and brain leptin receptor gene expression is not impaired in obesity.
Source: Eikelis N, et al. Brain leptin resistance in human obesity revisited. Regul Pept. 2007;139:45-51.
Leptin is a 16 KDA peptide predominantly produced by adipocytes. Leptin and its receptor are known to be involved in the regulation of energy balance. The data from animal studies, as well as our own observations of leptin overflow from the brain suggest that the central nervous system is a site of leptin synthesis. Using simultaneous arterio-venous blood sampling we here confirm that leptin is released from the brain into the internal jugular vein, and that release is greater in overweight men and in females compared to lean men, 467.3ng/min ± 160.4 and 1426 ng/min ± 769.3 vs 80.0ng/min ± 29.3, respectively (P < 0.05). Furthermore, we have examined the gene expression of leptin and its receptor isoforms by reverse transcription-polymerase chain reaction (RT-PCR) in human cadaver hypothalami across a broad range of adiposity.
Leptin gene expression was detected in a number of donors; the presence of detectable leptin mRNA was related to the mode of death rather than BMI or gender. We have also demonstrated gene expression of the 3 leptin receptor isoforms in the human hypothalamus. No relation was observed between the levels of hypothalamic expression of the long-signaling form of the leptin receptor and BMI. In summary, this study indicates that it is very difficult to explain human obesity on the basis of central nervous system leptin resistance, in that leptin is released in the brain, at a higher level in the obese, and brain leptin receptor gene expression is not impaired in obesity. (Regul Pept. 2007;139:45-51.)
Commentary
The discovery of leptin, a hormone produced primarily by fat cells, and its studies since 1994 has led us to seek a metabolic answer to our growing obesity problem. First was a speculation that "leptin deficiency" was the cause of obesity but this did not correlate with high levels of plasma leptin found in obese humans and animals. Then "leptin resistance" theory emerged to attempt to explain the obesity: leptin receptors were resistant to high levels of leptin and therefore must be producing signals to promote continued leptin production. This study used both human and cadaver data to investigate whether leptin resistance is related to obesity.
The data obtained from human subjects (obtained from arterial and internal jugular venous sampling) suggested that some leptin is actually made in the brain and released into the circulation. This finding was not expected as the authors were actually expecting leptin to go into the brain from systemic circulation. This is the first study to demonstrate and report brain synthesis of leptin but the implications of this finding are unclear.
Then cadaver hypothalami were examined for leptin gene expression and the presence of leptin receptors. There was no correlation between the BMI's of the cadavers and the level of leptin receptor expression in the CNS. These findings make "leptin resistance" explanation of the human obesity questionable.
It seems that leptin may not be the answer to obesity that everyone has been hoping for. For now, obesity is still a problem of excess intake of calories compared to expenditure, may it be metabolic or physiologic.
This study indicates that it is very difficult to explain human obesity on the basis of central nervous system "leptin resistance," in that leptin is released in the brain, and at a higher level in the obese, and brain leptin receptor gene expression is not impaired in obesity.Subscribe Now for Access
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