Glutamate release mediates leptin action on energy expenditure - PubMed (original) (raw)
Glutamate release mediates leptin action on energy expenditure
Yuanzhong Xu et al. Mol Metab. 2013.
Abstract
Restricting energy expenditure is an adaptive response to food shortage. Despite being insulated with massive amount of fat tissues, leptin-deficient mice lose the ability to maintain their body temperature and develop deep hypothermia, which can be suppressed by exogenous leptin, suggesting an important role for leptin in energy expenditure regulation. However, the mechanism underlying the leptin action is not clear. We generated mice with disruption of glutamate release from leptin receptor-expressing neurons by deleting vesicular glutamate transporter 2 in these neurons, and found that these mice developed mild obesity purely due to reduced energy expenditure, exhibited bouts of rapidly reduced energy expenditure, body temperature and locomotion. In addition, these mice exhibited lower energy expenditure and body temperature in response to fasting and were defective in leptin-mediated thermogenic action in brown adipose tissues. Taken together, our results identify a role for glutamate release in mediating leptin action on energy expenditure.
Keywords: Energy expenditure; Glutamate; Hypothermia; Leptin; Obesity.
Figures
Figure.1
Generation of mice with disruption of glutamate release from LepR-expressing neurons. (A–G) In situ hybridization for Vglut2 in the hypothalamus of Vglut2 flox/flox (CON) and LepR-iCre:Vglut2 flox/flox mice (CKO). Vglut2 expression signal was shown in the DMH and VMH of CON (A) and CKO (B) mice, and in the PMv of CON (C) and CKO (D) mice. (E–G) Statistical comparison in the number of Vglut2 positive neurons between CON and CKO mice for the VMH (E), DMH (F) and PMv (G). (H–J) p-STAT3 expression in the hypothalamus after leptin injection of CON (H) and CKO (I) mice. (J) Statistical comparison of p-STAT3 positive neurons between CON and CKO mice. (K–O) C-fos expression in the hypothalamus after leptin injection in the PVH of CON (K) and CKO mice (L), and in the DMH of CON(M) and CKO (N) mice. (O) Statistical comparison in the number of C-fos expressing neurons in the PVH, DHM and POA between CON and CKO mice. Scale bar=100 μM. ⁎P<0.05; ⁎⁎P<0.01. _n=_5–7; DMH: dorsal medial hypothalamus; VMH: ventromedial hypothalamus; PMv: premammillary nucleus, ventral part; PVH: paraventricular hypothalamus; fx: fornix.
Figure. 2
Disruption of glutamate release from LepR-expressing neurons leads to obesity and torpor like behavior. (A, B) Weekly body weight of CON and CKO mice measured from 4 weeks of age until 15 weeks of age in males (A, _n=_14–16) and females (B, _n=_11–14). (C) Body composition of males measured at 15 weeks of age. (D) Accumulative food intake measured in males during 5–6 weeks of age when there was no difference in body weight between genotypes. (E) O2 consumption of males (_n=_6–8) was measured during 5–6 weeks of age. Note a repeatable, rapid reduction in O2 consumption in early phase of the dark period (arrows). (F) Comparison of O2 consumption during the light and dark periods between CON and CKO mice. (G) Core body temperature (Tc) measured by E-mitter biotelemetry (_n=_5–7, 8–10 weeks old males). Note a period of rapid reduction in core body temperature during the early phase of the dark period (arrow), a similar time point with rapid reduction of O2 (F). (H) Comparison of locomotion during light and dark periods between CON and CKO mice. Note a significantly increased locomotion during the dark period in CKO mice. (I) Locomotion in 8–10 weeks old males (_n=_5–7). Note a period of rapid reduction in locomotion in the early phase of the dark period (arrow), a similar time point with rapid reduction of O2 consumption in (F) and Tc (G). ⁎P<0.05.
Figure. 3
Disruption of glutamate release from LepR neurons leads to defective responses to fasting and leptin in energy expenditure (EE). (A) Resting EE in 5–6 weeks old males (_n=_6–8) from 9 am to 3 pm of the test day with food removed. (B) Comparison in O2 consumption measured during the 6-hour resting period. (C) Tc in 8–10 weeks old male mice (_n=_5–7) with fasted from late light period to the end of the dark period. Note a reduction in Tc of CKO mice compared to CON mice during dark periods. (D) UCP1 expression in the iBAT at the end of fasting period. (E) Locomotion measured by E-mitter biotelemetry from the same mice in (C). Note a more drastic reduction in locomotion in CKO mice (arrow). (F) Net difference in locomotion in the dark period between fed and fast conditions in CON and CKO mice. Note a reduction of 2 counts/minute in CON mice in response to fasting while 12 counts/minute in CKO mice. (G, H) iBAT temperature in response to saline and leptin in CON (G) and CKO (H) male mice (8–10 weeks old, _n=5–6). Note that the injection procedure imposed a stress induced period of hyperthermia (both G and H). Compared to saline injection, leptin induced a period with higher temperature in iBAT of CON mice (G). In CKO mice, no difference in iBAT temperature produced by leptin administration (H). (I) FGF21 expression in liver at the end of the fasting period. ⁎_P<0.05.
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