Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight

Abstract

Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These "weight-reduced" phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state.

Figures

Figure 1

Schematic of protocol.

Figure 2

Effects of weight loss and leptin administration on circulating leptin concentrations. (A) 8 am plasma leptin concentrations at Wtinitial, Wt–10%, and Wt–10%lep. Circulating leptin concentrations were significantly lower at Wt–10%, than at Wtinitial or at Wt–10%lep. (B) Percent changes (mean ± SEM) from Wtinitial values in plasma leptin concentrations at Wt–10% and Wt–10%lep. *P < 0.05 compared with 0.

Figure 3

Subject characteristics. Administration of exogenous leptin to weight-reduced subjects ingesting an isocaloric diet was associated with a significant decline in body weight and fat mass but not fat-free mass. Data refer to 10 subjects: 5 males, 5 females; 7 obese, 3 never-obese. Mean ± SEM values at each weight plateau are presented in Supplemental Table 1 (supplemental material available online with this article; doi:10.1172/JCI25977DS1). *P < 0.05 versus Wtinitial; †P < 0.05 versus Wt–10%.

Figure 4

Energy expenditure and skeletal muscle. Percent change (mean ± SEM) from values at Wtinitial of energy expenditure, skeletal muscle work efficiency, and fuel utilization. Administration of leptin to weight-reduced subjects reversed the significant decline in TEE and NREE associated with maintenance of a 10% reduced body weight. Effects of weight loss and exogenous leptin on skeletal muscle gross mechanical work efficiency (kcal/min energy expended above resting per kcal/min work generated) and fuel utilization (derived from RQ; ref. 87) were only evident at low levels of work (bicycling to generate 10 W of power). Mean ± SEM values at each weight plateau are presented in Supplemental Table 1, and individual values are presented in Supplemental Figure 1. *P < 0.05 versus 0; †P < 0.05 versus Wt–10%. GME, gross mechanical efficiency.

Figure 5

Neuroendocrine function. Percent change (mean ± SEM) from values at Wtinitial of T3, T4, and TSH. Administration of leptin to weight-reduced subjects reversed the significant declines in circulating concentrations of T4 and T3, but not TSH, that are associated with the maintenance of a 10% reduced body weight. Mean ± SEM values at each weight plateau are presented in Supplemental Table 1. *P < 0.05 versus 0; †P < 0.05 versus Wt–10%.

Figure 6

Autonomic function. Percent change (mean ± SEM) from values at Wtinitial of autonomic nervous system tone. Administration of leptin to weight-reduced subjects reversed the significant declines in one 24-hour urinary epinephrine excretion and SNS tone (measured by heart rate analysis during serial pharmacological blockade), which are associated with maintenance of a 10% reduced body weight. No effect of leptin was noted on urinary dopamine excretion, on the significant decline in urinary norepinpehrine excretion, or on the significant increase in parasympathetic tone associated with maintenance of a 10% reduced body weight. Mean ± SEM values at each weight plateau are presented in Supplemental Table 1. *P < 0.05 versus 0; †P < 0.05 versus Wt–10%.