Effects of chronic leptin infusion on subsequent body weight and composition in mice: Can body weight set point be reset?

Abstract

Circulating leptin concentrations correlate with fat mass and signal the status of somatic energy stores to the brain. Previous studies suggest that diet-induced elevations of body weight increase body weight "set-point". To assess whether chronic hyperleptinemia is responsible for this shift in defended body weight, we elevated circulating leptin concentrations in lean mice to those comparable to diet-induced obese mice for eighteen weeks. We hypothesized that following cessation of leptin infusion, a higher body weight would be defended. Compared to saline-infused controls, leptin-infused mice had elevated circulating leptin concentrations, gained less weight, yet had similar metabolic rates. Following cessation of leptin administration, leptin-infused mice gained some weight yet plateaued at 5-10% below controls. These results suggest that, unlike mice rendered hyperleptinemic by diet-induced weight gain, leptin-infused mice do not subsequently "defend" a higher body weight, suggesting that hyperleptinemia per se does not mimic the CNS consequences of chronic weight gain.

Keywords: Body weight “set-point”; Leptin; Leptin resistance; Obesity.

Figure 1

Experimental Timeline. Experimental timeline of all three phases of the study. Following a 3 week acclimatization period at Columbia University, mice were nine weeks old at the start of the experiment. Mini-pumps containing increasing quantities of leptin were surgically replaced every two weeks during an 18-week infusion period (Phase 1). Blood was obtained by retro-orbital bleed following a 4-h fast eight days after each mini-pump switch during the 18 weeks of Phase 1 as well as well as 5, 41, and 118 days following removal of the final pump (see black circles).

Figure 2

Body weight, body composition, and circulating leptin concentration during Leptin Infusion phase (A–C) Mean (±sem) body weight (A) fat mass (B) and fat-free mass (C) of leptin- (LEP mice; n = 32; black diamond) or PBS- (PBS mice; n = 12; open diamonds) infused mice. Black circles represent mini-pump replacement surgeries (doses of leptin are noted below each circle in μg/day). Black line on bottom right represents 72 h indirect calorimetry measures for all mice. (D) Mean (±sem) serum leptin concentrations (ng/ml) at increasing leptin infusion rates (μg/day) of LEP and PBS groups collected from four-hour fasting serum obtained 7 days following mini-pump replacement surgery. * p < 0.05.

Figure 3

Energy expenditure, ambulatory activity, and respiratory during Leptin Infusion phase. Mean (±sem) non-adjusted (for body weight or composition) total energy expenditure (A), total activity (B), and respiratory quotient (C) of leptin- (LEP mice; n = 32; black diamond) or PBS- (PBS mice; n = 12; open diamond) infused mice. Gray shading represents lights off period. Mice spent 72 h in calorimeter; data was collected during the last 48 h for all three figures.

Figure 4

Body weight, food intake, and metabolic efficiency during Weight Regain phase. Mean (±sem) body weight (A) percent body weight change (B) 24-h food intake of low fat (10% kcal from fat) control diet (C) and 24-h feed efficiency (calculated by dividing 24-h weight change (g) by 24-h food intake (g)) (D) of leptin- (LEP mice; n = 32; black diamond) or PBS- (PBS mice; n = 12; open diamond) infused mice 30 days following removal of the terminal mini-pump.

Figure 5

Food intake during Diet Preference phase. Mean (±sem) kcal/24 h consumed of either low fat diet (LFD: 10% kcal from fat: dashed lines) or medium fat diet (MFD: 30% kcal from fat: solid lines) for either leptin- (LEP mice; n = 32; black diamond) or PBS- (PBS mice; n = 12; open diamond) infused mice.