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. 2008 Dec;8(6):459-67.
doi: 10.1016/j.cmet.2008.10.004.

Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis

Clémence Blouet  1 , Hiraku Ono, Gary J Schwartz
Affiliations

Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis

Clémence Blouet et al. Cell Metab. 2008 Dec.

Abstract

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 the assessment of MBH S6K activity as a therapeutic target in metabolic diseases.

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Figures

Figure 1
Figure 1. Refeeding and leptin induce MBH S6K phosphorylation
MBH S6K Thr389 phosphorylation (A) in 24h fasted (n=5) or 24h fasted and 3h refed (n=5) rats and (B) 30 min after bilateral MBH aCSF (n=4) or MBH leptin (n=4) injection (150 ng in 150 nl) in rats. All data are means ± SEM.
Figure 2
Figure 2. Bidirectional molecular targeting of MBH S6K activity is sufficient to alter food intake and body weight
(A) changes in body weight and (B) changes in food intake after MBH injection of CA S6K (n=12, filled triangle), DN S6K (n=13, filled square) or LACZ (n=18, open circle). (C) MBH NPY mRNA, (D) MBH AgRP mRNA and (E) MBH POMC mRNA levels normalized to that of actin in CA S6K, DN S6K, LACZ and LACZ pairfed controls (n=6–8). Cumulative food intake over 9 days is 231.7 ± 9.4, 275.27 ± 6.65 and 269.1 ± 7.4 in CA S6K, DN S6K and LACZ controls, respectively. All data are means ± SEM.
Figure 3
Figure 3. Constitutive activation of MBH S6K decreases energy expenditure
(A) food intake, (B) oxygen consumption, (C) respiratory quotient and (D) physical activity before (average of d-3 to d-1) and after (average of d5 to d7) MBH adenoviral injection in CA S6K (filled bar, n=4) or LACZ pair-fed controls (open bar, n=4). (E) Change in body weight in CA S6K (n=12, filled triangle) and LACZ pair-fed (open square, n=9). All data are means ± SEM.
Figure 4
Figure 4. Constitutive activation of MBH S6K increases thermogenesis during a cold challenge
(A) core temperature during a 5h cold challenge at −16 °C 7 days after adenoviral injection in CA S6K (filled triangle, n=6), LACZ (open circle, n=4) or LACZ pair-fed controls (open square, =4). Intrascapular brown adipose tissue UCP1 (B) mRNA level normalized to actin and (C) protein level normalized to actin in LACZ (n=7), LACZ pair-fed (n=7) and CA S6K rats (n=9). All data are means ± SEM.
Figure 5
Figure 5. Bidirectional alteration of MBH S6K activity modulates the metabolic and feeding response to a 24h fast
(A) changes in body weight after a 24h fast in LACZ (n=10), LACZ pair-fed (n=10), CA S6K (n=10) and DN S6K (n=10) rats. (B) 3h food intake following a 24h fast in LACZ (n=5), LACZ pair-fed (n=5), CA S6K (n=5) and DN S6K (n=5) rats. All data are means ± SEM.
Figure 6
Figure 6. Bidirectional molecular targeting of MBH S6K activity is sufficient to alter hypothalamic leptin sensitivity
(A) 24h change in body weight and (B) 24h food intake after MBH artificial-cerebrospinal fluid (open bar) vs. leptin (150 ng in 150 nl per side, filled bar) injections in LACZ (n=9), CA S6K (n=6) and DN S6K rats (n=5). All data are means ± SEM.
Figure 7
Figure 7. Constitutive activation of MBH S6K protects against adverse effects of a HFD
(A) Energy intake and (B) changes in body weight after MBH injection of CA S6K (n=6, filled triangle) or LACZ (n=6, open circle) and shift to a HFD. (C) fat mass (FM) in CA S6K (n=6, filled bar) or LACZ (n=6, open bar) rats before (day 3) and 10 days after (day 13) a shift to a HFD. (D), blood glucose and (E), plasma insulin during an oral glucose tolerance test (1g/kg) in LACZ (open circles, n=6) and CA S6K (filled squares, n=6) rats 10 days after a shift to a HFD. All data are means ± SEM.
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