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. 2011 Jun;121(6):2413-21.
doi: 10.1172/JCI43703. Epub 2011 May 23.

Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice

Michael M Scott  1 , Kevin W Williams, Jari Rossi, Charlotte E Lee, Joel K Elmquist
Affiliations

Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice

Michael M Scott et al. J Clin Invest. 2011 Jun.

Abstract

Leptin is an adipose-derived hormone that signals to inform the brain of nutrient status; loss of leptin signaling results in marked hyperphagia and obesity. Recent work has identified several groups of neurons that contribute to the effects of leptin to regulate energy balance, but leptin receptors are distributed throughout the brain, and the function of leptin signaling in discrete neuronal populations outside of the hypothalamus has not been defined. In the current study, we produced mice in which the long form of the leptin receptor (Lepr) was selectively ablated using Cre-recombinase selectively expressed in the hindbrain under control of the paired-like homeobox 2b (Phox2b) promoter (Phox2b Cre Lepr(flox/flox) mice). In these mice, Lepr was deleted from glucagon-like 1 peptide-expressing neurons resident in the nucleus of the solitary tract. Phox2b Cre Lepr(flox/flox) mice were hyperphagic, displayed increased food intake after fasting, and gained weight at a faster rate than wild-type controls. Paradoxically, Phox2b Cre Lepr(flox/flox) mice also exhibited an increased metabolic rate independent of a change in locomotor activity that was dependent on food intake, and glucose homeostasis was normal. Together, these data support a physiologically important role of direct leptin action in the hindbrain.

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Figures

Figure 1
Figure 1. Quantification of Phox2b Cre deletion of Lepr in the hindbrain.
Neurons immunoreactive for phospho–STAT-3 were counted after a 12-hour fast and leptin (5 mg/kg) given i.p. (A) Control flox mice showed significantly more NTS STAT-3+ cells than (B) the PC flox animals. aq, aqueduct. (C) Phox2b Cre deletion resulted in a 60%–70% reduction of phospho–STAT-3 expressing neurons (n = 4, P < 0.02). (D) Glp1 mRNA is expressed by the Phox2b Cre transgene expressing cells (arrows). Scale bar: 100 μm (A and B); 25 μm (D).
Figure 2
Figure 2. Phox2b Cre deletion of Lepr increases rate of weight gain.
(A) Weights of PC flox and flox mice were followed over time on chow diet (n = 20). Analysis of the rate of weight changes demonstrated a significant increase in rate of weight gain in the Lepr-deleted mice (95% confidence interval: PC flox [slope, 0.6095 to 0.7058 g of body weight per week] versus flox [slope, 0.5089 to 0.5961 g of body weight per week], P < 0.001). Individual data points suggest a trend toward significant difference in body weight at the end of the study (P < 0.07). (B) At 6 weeks of age, no difference in body composition was observed. (C) A trend toward an increase in body fat percentage was observed at the end of the body weight study, with PC flox–deleted mice showing an increase in adiposity (n = 10, P < 0.10).
Figure 3
Figure 3. Analysis of food intake, glucose homeostasis, and metabolic parameters.
(A) Phox2b Cre deletion of Lepr resulted in an increase in food intake in ad libitum fed mice, (B) while increasing food intake in fasted mice (n = 10). (C) An increase in metabolic rate (data were raised to the power of 0.75) was observed during the dark phase in the PC flox–deleted mice (n = 10, P < 0.05). (D) Deletion of Lepr in the NTS produced no alterations in respiratory exchange rate (n = 10), indicating that fuel preference was unaltered. (E) No difference in locomotor activity was detected between flox and PC flox mice (n = 10). (F) Glucose and (G) insulin tolerance tests showed no difference in glucose handling or in the response to insulin in the Lepr-deleted mice (n = 10).
Figure 4
Figure 4. Elevated metabolic rate of PC flox mice is normalized during fasting.
During the initial 3-day period prior to fasting, mice were fed ad libitum. (A) PC flox mice exhibited an elevation in metabolic rate when compared with that of control flox mice. (B) During the fasting period, PC flox mice showed no difference in metabolic rate when compared with that of control flox mice. (C and D) Locomotor activity was unchanged in both groups.
Figure 5
Figure 5. Analysis of food intake and metabolic parameters on HFD.
Hindbrain leptin deletion produced no change in (A) food intake, (B) locomotor activity, (C) fuel preference, (D) metabolic rate, or (E) rate of weight change when challenged with HFD-fed diet ad libitum.
Figure 6
Figure 6. Effect of hindbrain Lepr deletion on CCK- and leptin-induced food intake and body weight.
(A) CCK was injected i.p. (20 μg/kg) in PC flox and flox control mice after an overnight fast. Both PC flox and control flox mice consumed significantly less food over a 24-hour period (1-way ANOVA, P < 0.05) compared with that of saline-injected controls. There was no difference between genotypes. Leptin, delivered by osmotic minipump at a rate of 1 μg/d for 7 days, significantly reduced (B) food intake and (C) body weight in both PC flox and control flox mice, relative to that of controls.
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