Mediobasal Hypothalamic p70 S6 Kinase 1 Modulates the Control of Energy Homeostasis

Abstract

SUMMARY p70 S6 kinase 1 (S6K) is a major downstream effector of the mammalian target of rapamycin (mTOR), primarily implicated in the control of protein synthesis, cell growth and proliferation. Here we demonstrate that specific bidirectional molecular targeting of mediobasal hypothalamic (MBH) S6K activity in rats is sufficient to significantly alter food intake, body weight, hypothalamic orexigenic neuropeptide expression, hypothalamic leptin sensitivity and the metabolic and feeding responses to a fast. In addition, adenoviral-mediated constitutive activation of MBH S6K improved cold tolerance and protected against high-fat diet induced overeating, fat deposition and insulin resistance. Our results provide direct evidence that MBH S6K activity bidirectionally drives behavioral and metabolic determinants of energy balance, and promote its assessment as a therapeutic target in metabolic diseases.

mTORC1 signaling in energy balance and metabolic disease

“…Recent studies have shown that hypothalamic mTORC1 signaling is critically involved in the development of this central resistance, 49,50,52 although future investigations will need to address the actual molecular, electrophysiological and structural events underlying this phenomenon. Nevertheless, although the pathway seems to have a protective role within the hypothalamus during diet-induced obesity, its chronic activation in peripheral tissues has been identified to be detrimental and associated with insulin resistance.…”

“…16 Importantly, mice lacking S6K1 (S6K1 À/À ) are resistant to the anorectic action of mTORC1 and obesity C Catania et al leptin, 49 thus implying that S6K1 has a critical role in mediating leptin's action on energy balance. Accordingly, Blouet et al 50 have recently demonstrated that adenovirusmediated constitutive activation of S6K1 in the rat MBH facilitates leptin-induced anorexia. In fact, MBH S6K1 activity is per se sufficient to decrease body weight, by primarily changing food intake through reduced neuropeptide Y and agouti-related peptide mRNA expression.…”

“…50 Rats with constitutive activation of MBH S6K1 also seem protected against high-fat diet (HFD)-induced overeating and insulin resistance. 50 However, apparently in contrast with these findings, recent data also indicate that MBH S6K1 activity decreases MBH insulin signaling, an effect leading to hepatic insulin resistance. 51 This might suggest that within the MBH, intracellular pathways that regulate food intake and glucose homeostasis might diverge Figure 1 Regulation of the mTOR complex 1 (mTORC1) pathway.…”

“…In fact, MBH S6K1 activity is per se sufficient to decrease body weight, by primarily changing food intake through reduced neuropeptide Y and agouti-related peptide mRNA expression. 50 Moreover, bidirectional regulation of MBH S6K1 leads to complementary bidirectional changes in adaptive thermogenesis, thus suggesting that the hypothalamic S6K1 regulates the sympathetic drive to the brown adipose tissue (BAT). 50 Rats with constitutive activation of MBH S6K1 also seem protected against high-fat diet (HFD)-induced overeating and insulin resistance.…”

“…50 Moreover, bidirectional regulation of MBH S6K1 leads to complementary bidirectional changes in adaptive thermogenesis, thus suggesting that the hypothalamic S6K1 regulates the sympathetic drive to the brown adipose tissue (BAT). 50 Rats with constitutive activation of MBH S6K1 also seem protected against high-fat diet (HFD)-induced overeating and insulin resistance. 50 However, apparently in contrast with these findings, recent data also indicate that MBH S6K1 activity decreases MBH insulin signaling, an effect leading to hepatic insulin resistance.…”