Effects of Leptin on Corticotropin-Releasing Factor (CRF) Synthesis and CRF Neuron Activation in the Paraventricular Hypothalamic Nucleus of Obese (ob/ob) Mice

Abstract

The effects of leptin on the levels of CRF messenger RNA (mRNA) in the paraventricular hypothalamic nucleus (PVN), on the activation of the PVN CRF cells, and on the plasma levels of corticosterone were investigated in lean (+/?) and obese (ob/ob) C57BL/6J male mice. Murine leptin was s.c. infused using osmotic minipumps. The treatment period extended to 7 days, and the daily dose of leptin delivered was 100 microg/kg. The mice were killed either in a fed state or following 24 h of total food deprivation. The starvation paradigm was employed to enhance the activity of the hypothalamic-pituitary-adrenal axis in obese mice. In situ hybridization histochemistry was performed to determine the PVN levels of CRF mRNA and the arcuate nucleus levels of neuropeptide Y mRNA. The activity of the PVN CRF cells was estimated from the number of PVN cells colocalizing CRF mRNA and the protein Fos. Leptin led to a reduction in body weight gain and fat deposition. These effects were seen in both +/? and ob/ob mice and were observed to be particularly striking in obese mutants, in which leptin also caused an important reduction in food intake. Leptin also was found to affect plasma levels of corticosterone. It lowered the high corticosterone levels of obese mutants, an effect that appeared more evident in food-deprived than in fed mice. Finally, leptin prevented the induction of CRF synthesis in the PVN and the activation of the PVN CRF neurons observed in food-deprived ob/ob mice and hindered the elevation of arcuate nucleus neuropeptide Y synthesis in ob/ob mice. Together these results suggest a role for leptin in the excessive response of the hypophysiotropic CRF system of the ob/ob mouse.

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

“…For example, leptin treatment blocks elevation of ACTH and corticosterone levels following restraint [46] and ether stress [47]. Furthermore, leptin decreases mRNA expression of CRH in the PVN [47][48][49] and CRH release from the hypothalamus [50]. These findings suggest that the inhibitory effect of leptin on ACTH and corticosterone is probably mediated by hypothalamic CRH.…”

Biological Alterations in Depression

“…Lu et al, 2006). In response to stressful events, leptin suppresses CRH, ACTH, and corticosterone secretion, suggesting a direct impact of leptin on the HPA axis (Ahima et al, 1996;Heiman et al, 1997;Huang et al, 1998). In addition, leptin-deficient ob/ob mice display altered Slc6a4 expression (Collin et al, 2000), decreased neuronal and glial cells, and reduced brain weight and cortical volume (Ahima 1999, Stepan 1999, further supporting the role of leptin in MDD.…”

“…Additionally, insulin regulates monoamine uptake and metabolism, phosphoinositol turnover, as well as norepinephrine and dopamine transporter mRNA levels (Craft & Watson, 2004). It has been shown that insulin can recruit GABA receptors (Wan et al, 1997) and promote internalization ofamino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, which suggests that insulin plays a critical role in neuronal signaling and synaptic plasticity (Huang et al, 1998). Interestingly, brain volume abnormalities and neurocognitive deficits commonly found in MDD patients have been observed in individuals with diabetes mellitus (DM), suggesting overlapping pathophysiology between MDD and DM (McIntyre et al, 2010).…”

True

“…Consistent with this view are results showing that CRH mRNA expression within the hypophysiotropic neurons is not decreased in unrestrictedly fed obese faafa Zucker rats and obaob mice and is even induced in these rodents following food deprivation. 41,46 In addition, recent studies have shown that leptin can blunt the synthesis of CRH within the PVH. Leptin has for instance been reported to block both the CRH synthesis induced by food deprivation in obese obaob mice 46 and the CRH secretion from isolated rat hypothalami stimulated by glucose deprivation.…”