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Phosphodiesterase‐3B‐cAMP Pathway of Leptin Signalling in the Hypothalamus is Impaired During the Development of Diet‐Induced Obesity in FVB/N Mice
Author(s) -
Sahu M.,
Anamthathmakula P.,
Sahu A.
Publication year - 2015
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12266
Subject(s) - medicine , endocrinology , leptin , hypothalamus , anorectic , diet induced obese , chemistry , biology , obesity , insulin resistance , body weight
The phosphodiesterase‐3 B ( PDE 3B)‐ cAMP pathway plays an important role in transducing the action of leptin in the hypothalamus. Obesity is usually associated with hyperleptinaemia and resistance to anorectic and body weight‐reducing effects of leptin. To determine whether the hypothalamic PDE 3B‐ cAMP pathway of leptin signalling is impaired during the development of diet‐induced obesity ( DIO ), we fed male FVB / N mice a high‐fat diet ( HFD : 58% kcal as fat) or low‐fat diet ( LFD : 6% kcal as fat) for 4 weeks. HFD fed mice developed DIO in association with hyperphagia, hyperleptinaemia and hyperinsulinaemia. Leptin (i.p.) significantly increased hypothalamic PDE 3 B activity and phosphorylated (p)‐ A kt levels in LFD ‐fed but not in HFD ‐fed mice. However, basal p‐ A kt levels in hypothalamus were increased in DIO mice. Additionally, amongst six‐microdissected brain nuclei examined, leptin selectively decreased cAMP levels in the arcuate nucleus ( ARC ) of LFD ‐fed mice but failed to do so in HFD ‐fed mice. We next tested whether both the PBE 3 B and A kt pathways of leptin signalling remained impaired in DIO mice on the HFD for 12 weeks (long‐term). DIO mice were hyperinsulinaemic and hyperleptinaemic in association with impaired glucose and insulin tolerance. Although, in LFD ‐fed mice, leptin significantly increased PDE 3 B activity and p‐ A kt levels in the hypothalamus, it failed to do so in HFD ‐fed mice. Also, basal p‐ A kt levels in the hypothalamus were increased in DIO mice and leptin had no further effect. Similarly, immunocytochemistry showed that leptin increased the number of p‐ A kt‐positive cells in the ARC of LFD ‐fed but not in HFD ‐fed mice, and there was an increased basal number of p‐ A kt positive cells in the ARC of DIO mice. These results suggest that the PDE 3 B ‐ cAMP ‐ and A kt‐pathways of leptin signalling in the hypothalamus are impaired during the development of DIO . Thus, a defect in the regulation by leptin of the hypothalamic PDE 3 B ‐ cAMP pathway and A kt signalling may be one of the mechanisms of central leptin resistance and the development of DIO .