Hormonal
Chronic elevation of hypothalamic leptin tone, as seen in diet-induced obesity and aging, leads to central leptin resistance primarily through defects in the PI3K-PDE3B-cAMP signaling pathway rather than the JAK2-STAT3 pathway.
Obesity is not caused by a lack of leptin; in fact, obese individuals often have high levels of it. The problem is that the brain stops listening to the signal due to a specific signaling pathway defect (PI3K-PDE3B-cAMP). Therefore, simply increasing leptin (via supplements or injections) is unlikely to work for weight loss in obese individuals because the underlying resistance mechanism remains. Treatment strategies need to address the signaling defect, not just hormone levels.
Interestingly, hypothalamic neurons may develop leptin resistance despite an intact JAK2-STAT3 signaling path... a defective PDE3B-cAMP pathway of leptin signaling in the hypothalamus was evident... These findings suggest that this rat model of central leptin infusion can be used to elucidate mechanism of central leptin resistance, and that leptin signaling through the P13K-PDE3B-cAMP pathway in the hypothalamus is critical
Why this rating
The paper is a minireview citing multiple primary studies (references 78, 92, 93, 116-119) demonstrating the pathway in rodent models.
Source
Minireview: A Hypothalamic Role in Energy Balance with Special Emphasis on Leptin
Abhiram Sahu · Endocrinology · 2004
DOI 10.1210/en.2004-0032
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