Tub Has a Key Role in Insulin and Leptin Signaling and Action In Vivo in Hypothalamic Nuclei

Prada, Patrícia O.; Quaresma, Paula G.F.; Caricilli, Andréa M.; Santos, Amilton dos; Guadagnini, Dioze; Morari, Joseane; Weissmann, Laís; Ropelle, Eduardo Rochete; Carvalheira, José B.C.; Velloso, Lı́cio A.; Saad, Mário José Abdalla

doi:10.2337/db11-1388

Cited by 29 publications

(23 citation statements)

References 51 publications

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“…After the recovery period of ten to 14 days, the icv location of the cannula was confirmed by drinking response after angiotensin II injection [57]. Mice with indwelling lateral cerebroventricular (LCV) cannula were fasted 22–24 hours and injected icv with insulin (4.4 mU/2μl) [58,59], leptin (4 μg/2μl) or saline (2μl). After 30 minutes, the mice were sacrificed and the MBH were dissected out, frozen in liquid nitrogen and kept at −80°Cuntil processed for protein extraction to measure PDE3B activity and p-AKT and p-STAT3 levels as described above.…”

Section: Methodsmentioning

confidence: 99%

Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice

Sahu

Anamthathmakula²,

Sahu³

2016

Neuroendocrinology

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Background: Insulin action in the hypothalamus plays a critical role in the regulation of energy homeostasis, yet the intracellular signaling mechanisms mediating insulin action are incompletely understood. Although phosphodiesterase 3B (PDE3B) mediates insulin action in the adipose tissue and it is highly expressed in the hypothalamic areas implicated in energy homeostasis, its role, if any, in mediating insulin action in the hypothalamus is unknown. We tested the hypothesis that insulin action in the hypothalamus is mediated by PDE3B. Methods: Using enzymatic assay, we examined the effects of peripheral or central administration of insulin on hypothalamic PDE3B activity in adult mice. Western blotting and immunohistochemistry also examined p-Akt and p-STAT3 levels in the hypothalamus. Effects of leptin on these parameters were also compared. We injected cilostamide, a PDE3 inhibitor, prior to central injection of insulin and examined the 12- to 24-hour food intake and 24-hour body weight. Finally, we examined the effect of cilostamide on insulin-induced proopiomelanocortin (Pomc), neurotensin (Nt), neuropeptide Y (Npy) and agouti-related peptide (Agrp) gene expression in the hypothalamus by qPCR. Results: Peripheral or central injection of insulin significantly increased PDE3B activity in the hypothalamus in association with increased p-Akt levels but without any change in p-STAT3 levels. However, leptin-induced increase in PDE3B activity was associated with an increase in both p-Akt and p-STAT3 levels in the hypothalamus. Prior administration of cilostamide reversed the anorectic and body weight-reducing effects as well as stimulatory effect of insulin on hypothalamic Pomc mRNA levels. Insulin did not alter Nt, Npy and Agrp mRNA levels. Conclusion: Insulin induction of hypothalamic PDE3B activity and the reversal of the anorectic and body weight-reducing effects and stimulatory effect of insulin on hypothalamic Pomc gene expression by cilostamide suggest that activation of PDE3B is a novel mechanism of insulin signaling in the hypothalamus.

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Section: Methodsmentioning

confidence: 99%

Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice

Sahu

Anamthathmakula²,

Sahu³

2016

Neuroendocrinology

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“…CAY or vehicle were injected through intracerebroventricular (ICV) cannulation in obese mice twice a day (0800 h and 1700 h) for 5 days. In another set of animals, we inhibited the expression of IKKe by small interfering RNA ( (27). Mice were allowed to adapt 2 days before.…”

Section: Ikk« Inhibitionmentioning

confidence: 99%

“…Hypothalami were removed and homogenized in buffer as described previously (27). Phospho-IR, UCP-1, PEPCK, phospho-JAK2, phospho-STAT3, and phospho-IKKa/b antibodies were from Santa Cruz Technology (Santa Cruz, CA).…”

Section: Immunoblottingmentioning

confidence: 99%

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IKKε Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity

et al. 2014

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IKK epsilon (IKK«) is induced by the activation of nuclear factor-kB (NF-kB). Whole-body IKK« knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKK« is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKK« in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-kB activation in this tissue, relieving the inflammatory environment. Inhibition of IKK« activity, but not TBK1, reduced IRS-1 Ser307 phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKK« may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism.

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“…Obesity has been associated with hypothalamic insulin resistance and hyperphagia (6,13). Previous research showed consumption of a lard-enriched diet for 16 weeks increased IR serine phosphorylation, followed by higher expression of proinflammatory proteins in the hypothalamus of rats (14).…”

Section: Introductionmentioning

confidence: 99%

Deleterious effects of lard-enriched diet on tissues fatty acids composition and hypothalamic insulin actions

Dornellas

Watanabe

Pimentel

et al. 2015

Prostaglandins, Leukotrienes and Essential Fatty Acids

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Tub Has a Key Role in Insulin and Leptin Signaling and Action In Vivo in Hypothalamic Nuclei

Cited by 29 publications

References 51 publications

Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice

Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice

IKKε Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity

Deleterious effects of lard-enriched diet on tissues fatty acids composition and hypothalamic insulin actions

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