at the CNIC

Category: Publications (Page 1 of 12)

Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight

Vítor Ferreira, Cintia Folgueira, Maria Guillén, Pablo Zubiaur, Marcos Navares, Assel Sarsenbayeva, Pilar López Larrubia, Jan W. Eriksson, Maria J. Pereira,Francisco Abad-Santos, Guadalupe Sabio, Patricia Rada & Ángela M. Valverde.

Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity.

Olanzapine injection effects on AMPK phosphorylation (Image: Cintia Folgueira).

Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed.

Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain.

Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.

MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation

Rafael Romero-Becerra, Alfonso Mora, Elisa Manieri, Ivana Nikolic, Ayelén Melina Santamans, Valle Montalvo-Romeral, Francisco Miguel Cruz, Elena Rodríguez, Marta León, Luis Leiva-Vega, Laura Sanz, Víctor Bondía, David Filgueiras-Rama, Luis Jesús Jiménez-Borreguero, José Jalife, Barbara Gonzalez-Teran & Guadalupe Sabio.

Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6.

Cardiac hypertrophy under the microscope.
Cardiac hypertrophy in a heart lacking MKK6 (Image: Bárbara González-Terán).

Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin.

In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

Veronica Pena-Leon, Cintia Folgueira, Silvia Barja-Fernández, Raquel Pérez-Lois, Natália Da Silva Lima, Marion Martin, Violeta Heras, Sara Martinez-Martinez, Paola Valero, Cristina Iglesias, Mannon Duquenne, Omar Al-Massadi, Daniel Beiroa, Yara Souto, Miguel Fidalgo, Rasika Sowmyalakshmi, Diana Guallar, Juan Cunarro, Cecilia Castelao, Ana Senra, Patricia González-Saenz, Rocío Vázquez-Cobela, Rosaura Leis, Guadalupe Sabio, Helge Mueller-Fielitz, Markus Schwaninger, Miguel López, Sulay Tovar, Felipe F Casanueva, Emmanuel Valjent, Carlos Diéguez, Vincent Prevot, Rubén Nogueiras & Luisa M Seoane.

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown.

Prolonged breastfeeding increases interscapular temperature (Image: Cintia Folgueira).

Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta.

Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

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