Targeted leptin receptor blockade: role of ventral tegmental area and nucleus of the solitary tract leptin receptors in body weight homeostasis

Matheny, Michael; Strehler, Kevin Y. E.; King, Michael A.; Tümer, Nihal; Scarpace, Philip J.

doi:10.1530/joe-13-0455

Cited by 10 publications

(9 citation statements)

References 18 publications

(49 reference statements)

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“…It appears that fat stores were almost if not completely depleted after 2 wk of leptin gene delivery in both intact and denervated rats. This rapid loss in fat mass corroborates previously observed catabolic response to leptin (22). Given the very limited amount of white adipose tissue (WAT) that remained at the end our studies, future experiments should focus on analyzing WAT lipolysis and remodeling at earlier time points, before depletion of WAT stores.…”

Section: P-stat3 Gapdhsupporting

confidence: 89%

iBAT sympathetic innervation is not required for body weight loss induced by central leptin delivery

Côté

Sakarya

Green

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

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We evaluated the contribution of brown adipose tissue (BAT) sympathetic innervation on central leptin-mediated weight loss. In a short- and long-term study, F344BN rats were submitted to either a denervation of interscapular BAT (Denervated) or a sham operation (Sham). Animals from each group received the Ob (Leptin) or green fluorescent protein (GFP; Control) gene through a single injection of recombinant adeno-associated virus delivered centrally. Changes in body weight were recorded for 14 or 35 days, after which adipose tissues and skeletal muscles were weighed. In both studies, hypothalamic phosphorylated STAT3 (P-STAT3) was significantly higher in Sham-Leptin and Denervated-Leptin groups compared with their respective Control groups ( P < 0.01), indicating that leptin signaling was enhanced at the end point. We measured uncoupling protein 1 (UCP1), a marker of BAT thermogenic activity, and found a significant induction in Leptin in Sham animals ( P < 0.001) but not in Denervated animals, demonstrating that BAT UCP1 protein was only induced in Sham rats. Both Sham-Leptin and Denervated-Leptin rats lost ~15% of their initial body weight ( P < 0.001) by day 14 and reached a maximum of 18% body weight loss that stabilized over week 3 of treatment, indicating that sympathetic outflow to BAT is not required for leptin-mediated weight loss. In summary, interscapular BAT (iBAT) denervation did not prevent body weight loss following central leptin gene delivery. The present data show that sympathetic innervation of iBAT is not essential for leptin-induced body weight loss.

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Section: P-stat3 Gapdhsupporting

confidence: 89%

iBAT sympathetic innervation is not required for body weight loss induced by central leptin delivery

Côté

Sakarya

Green

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

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“…We also evaluated the pSTAT3/STAT3 levels, a marker for leptin signalling, because we demonstrated previously that leptin receptor blockade disrupts body weight regulation (Matheny et al 2014). Although there was a tendency toward a decline of leptin signalling in older versus younger rats, neither baseline levels nor levels after tempol treatment were significantly different.…”

Section: Discussionmentioning

confidence: 99%

Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway

Toklu

Scarpace

Sakarya

et al. 2017

Appl. Physiol. Nutr. Metab.

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Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5′AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.

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“…Of interest, our previous work shows that HIV-1 transgenic rats exhibit an inherent reduction of baseline body weight relative to control fisher 344 rats ( Midde et al, 2011 ). The VTA of the midbrain is important for food consumption and body weight ( Koyama et al, 2013 ; Matheny et al, 2014 ) and plays a critical role in food intake and reward ( Mietlicki-Baase et al, 2015 ). Therefore, one implication of our present findings is that Tat-induced impairment of the DA system within the VTA may, at least in part, result in the reduction of food consumption and body weight noted in HIV-1 transgenic rats ( Peng et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Intra-ventral tegmental area HIV-1 Tat1–86 attenuates nicotine-mediated locomotor sensitization and alters mesocorticolimbic ERK and CREB signaling in rats

et al. 2015

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Cigarette smoking prevalence in the HIV-positive individuals is profoundly higher than that in the HIV-negative individuals. We have demonstrated that HIV-1 transgenic rats exhibit attenuated nicotine-mediated locomotor activity, altered cAMP response element binding protein (CREB) and extracellular regulated kinase (ERK1/2) signaling in the mesocorticolimbic regions. This study investigated the role of HIV-1 transactivator of transcription (Tat) protein in the alterations of nicotine-mediated behavior and the signaling pathway observed in the HIV-1 transgenic rats. Rats received bilateral microinjection of recombinant Tat1–86 (25 μg/side) or vehicle directed at ventral tegmental area (VTA) followed by locomotor testing in response to 13 daily intravenous injections of nicotine (0.05 mg/kg, freebase, once/day) or saline. Further, we examined the phosphorylated levels of CREB (pCREB) and ERK1/2 (pERK1/2) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and VTA. Tat diminished baseline activity in saline control rats, and attenuated nicotine-induced behavioral sensitization. Following repeated saline injection, the basal levels of pERK1 in the NAc and VTA and pERK2 in VTA were lower in the vehicle control group, relative to the Tat group. After repeated nicotine injection, pERK1 in NAc and VTA and pERK2 in VTA were increased in the vehicle group, but not in the Tat group. Moreover, repeated nicotine injections decreased pCREB in the PFC and VTA in the Tat group but not in the vehicle group. Thus, these findings indicate that the direct injection of Tat at the VTA may mediate CREB and ERK activity in response to nicotine-induced locomotor activity.

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Targeted leptin receptor blockade: role of ventral tegmental area and nucleus of the solitary tract leptin receptors in body weight homeostasis

Cited by 10 publications

References 18 publications

iBAT sympathetic innervation is not required for body weight loss induced by central leptin delivery

iBAT sympathetic innervation is not required for body weight loss induced by central leptin delivery

Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway

Intra-ventral tegmental area HIV-1 Tat1–86 attenuates nicotine-mediated locomotor sensitization and alters mesocorticolimbic ERK and CREB signaling in rats

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