Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress
- University of Massachusetts Medical School, United States
- Beth Israel Deaconess Medical Center, United States
- Harvard Medical School, United States
- Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
- Yale University School of Medicine, United States
- Howard Hughes Medical Institute, Yale University School of Medicine, United States
Figures
Figure 1 with 3 supplements
JNK3 deficiency causes hyperphagia and obesity.
(A) WT mice were fed (4 wk) a chow diet (CD) or a high-fat diet (HFD). The body mass change at 24 hr post-injection (i.p. with solvent (PBS) or 2.5 mg/kg leptin) was measured (mean ± SEM; n=8; ***p<0…
Figure 1—figure supplement 1
JNK3 deficiency causes obesity without changes in energy expenditure.
(A) Organ mass of CD-fed and HFD-fed (12 wk) WT and Mapk10-/- mice was measured (mean ± SEM; n=10~12; *p<0.05; ***p<0.001). (B) CD-fed and HFD-fed (4 wk) WT and Mapk10-/- mice were examined using …
Figure 1—figure supplement 2
Time course of the development of hyperphagia in HFD-fed JNK3-deficient mice.
(A) Metabolic cage analysis of WT and Mapk10-/- mice fed a HFD. The amount of food consumed 7pm – 7am each day was measured (mean ± SEM; n=6; *p<0.05; **p<0.01). (B) Fat and lean body mass of WT and …
Figure 1—figure supplement 3
Increased food consumption is required for obesity caused by JNK3 deficiency in HFD-fed mice.
WT and Mapk10-/- mice were fed a HFD ad libitum. A second group of Mapk10-/- mice were pair-fed with the WT mice. The change in body mass was measured (mean ± SEM; n= 6; **p<0.01).
Figure 2
JNK3 deficiency promotes and adipose tissue inflammation and insulin resistance.
(A-F) Hyperinsulinemic-euglycemic clamps were performed on CD-fed or HFD-fed (3 wk) WT and Mapk10-/- mice. Clamp hepatic glucose production (A), hepatic insulin action (B), glucose turnover (C), …
Figure 3
JNK3 deficiency causes a selective defect in AgRP neurons.
(A) HFD-fed (4 wk) WT and Mapk10-/- mice were treated by intracerebroventricular administration of 5 µg leptin or solvent (Control). The change in body mass at 24 hr post-treatment was measured …
Figure 4 with 2 supplements
JNK3 deficiency in leptin-responsive neurons causes HFD-induced hyperphagia and obesity.
(A) The total body mass gain of CD-fed and HFD-fed mice was examined (mean ± SEM; n = 10~25; *p<0.05; **p<0.01). JNK3 deficiency in LEPRb+ neurons was studied by comparing Leprb-cre control mice …
Figure 4—figure supplement 1
Establishment of Mapk10LoxP/LoxPmice.
(A) The strategy employed to target the Mapk10 locus (exons 6–9) by homologous recombination is illustrated. Restriction sites and PCR amplimers are indicated. Abbreviations: NEO, neomycin …
Figure 4—figure supplement 2
JNK3 deficiency in leptin-responsive neurons causes obesity.
(A) Organ mass of CD-fed and HFD-fed (16 wk) LepRb-cre (LeprWT) and LepRb-cre Mapk10Loxp/LoxP(Lepr∆J3) mice was measured (mean ± SEM; n=10~12; **p<0.01; ***p<0.001). (B) CD-fed and HFD-fed (4 wk) …
Figure 5 with 1 supplement
JNK3 in AgRP neurons, but not POMC neurons, regulates food consumption.
(A,B) Food consumption by CD-fed and HFD-fed (4 wk) mice was measured (mean ± SEM; n = 8; *p<0.05). JNK3 deficiency in POMC neurons was studied by comparing Pomc-cre control mice (PomcWT mice) and Po…
Figure 5—figure supplement 1
Effect of JNK3 deficiency in AgRP and POMC neurons on energy expenditure.
(A) CD-fed and HFD-fed (4 wk) AgrpWT and Agrp∆J3 mice mice were examined using metabolic cages to measure VO2, VCO2, and energy expenditure (mean ± SEM; n=8; p>0.05). (B) CD-fed and HFD-fed (4 wk) …
Figure 6 with 1 supplement
JNK3 regulates excitatory transmission onto AgRP neurons.
(A,B) Mapk10+/+ Npy-GFP and Mapk10-/- Npy-GFP mice were fed a HFD (3 wk) prior to electrophysiological recording of mIPSC from AgRP neurons. (C,D) mIPSC frequency (freq.) and amplitude (amp.) in …
Figure 6—figure supplement 1
The AMPA receptor antagonist DNQX blocks mEPSCs in AgRP neurons.
mEPSCs of arcuate AgRP neurons from Npy-GFP mice were recorded under baseline conditions (perfusion with aCSF) and following addition of 10 µM DNQX. The data presented are representative of three …
