Leptin regulation of core body temperature involves mechanisms independent of the thyroid axis

Abstract

The ability to maintain core temperature within a narrow range despite rapid and dramatic changes in environmental temperature is essential for the survival of free-living mammals, and growing evidence implicates an important role for the hormone leptin. Given that thyroid hormone plays a major role in thermogenesis and that circulating thyroid hormone levels are reduced in leptin-deficient states (an effect partially restored by leptin replacement), we sought to determine the extent to which leptin's role in thermogenesis is mediated by raising thyroid hormone levels. To this end, we 1) quantified the effect of physiological leptin replacement on circulating levels of thyroid hormone in leptin-deficient ob/ob mice, and 2) determined if the effect of leptin to prevent the fall in core temperature in these animals during cold exposure is mimicked by administration of a physiological replacement dose of triiodothyronine (T₃). We report that, as with leptin, normalization of circulating T₃ levels is sufficient both to increase energy expenditure, respiratory quotient, and ambulatory activity and to reduce torpor in ob/ob mice. Yet, unlike leptin, infusing T₃ at a dose that normalizes plasma T₃ levels fails to prevent the fall of core temperature during mild cold exposure. Because thermal conductance (e.g., heat loss to the environment) was reduced by administration of leptin but not T₃, leptin regulation of heat dissipation is implicated as playing a uniquely important role in thermoregulation. Together, these findings identify a key role in thermoregulation for leptin-mediated suppression of thermal conduction via a mechanism that is independent of the thyroid axis.

Keywords: body temperature; energy expenditure; energy intake; leptin; thermal conductance; thermoregulation; thyroid hormone.

Fig. 1.

Effect of a physiological dose of T₃ on core temperature in ob/ob mice during mild cold exposure. Schematic of study design (A), photoperiod-averaged 24-h core temperature in adult male ob/ob mice housed at under room temperature conditions [22°C; Baseline: Group 1 (blue), Group 2 (red); B] or treated systemically with either veh [Group 1 (blue)] or a physiological dose of T₃ [Group 2 (red)] and subjected to mild cold exposure (14°C; C). The mean change in photoperiod-averaged 24-h core temperature (D) and mean change in core temperature during the dark cycle, light cycle, and 24-h period (E) over all days of treatment in veh-treated mice housed under room temperature conditions (22°C; Baseline) relative to veh- and T₃-treated mice subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. T₃. ns, not significant; T₃, triiodothyronine; veh, vehicle.

Fig. 2.

Time-course effect of a physiological dose of T₃ on core body temperature and measures of energy homeostasis during cold exposure. Core body temperature (A), heat production (B), ambulatory activity (C), and energy intake (D) in adult male ob/ob mice treated systemically with either veh or T₃ over time and subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. 14°C veh. T₃, triiodothyronine; veh, vehicle.

Fig. 3.

Effect of a physiological dose of T₃ on energy expenditure, respiratory quotient, and ambulatory activity in ob/ob mice during mild cold exposure. Photoperiod-averaged 24-h profiles and mean dark and light cycle measures of heat production (A–C), respiratory quotient (RQ; D–F), and ambulatory activity (G–I) using indirect calorimetry, respectively, in adult male ob/ob mice housed under room temperature conditions [22°C; Baseline: Group 1 (blue), Group 2 (red)] or treated systemically with either veh [Group 1 (blue)] or a physiological dose of T₃ [Group 2 (red)] and subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. 22°C paired Baseline; #P < 0.05 vs. 14°C veh. T₃, triiodothyronine; veh, vehicle.

Fig. 4.

Effect of a physiological dose of T₃ on energy intake and thermal conductance in ob/ob mice during mild cold exposure. Photoperiod-averaged 24-h energy intake (A and B), mean energy intake during the dark cycle, light cycle, and 24-h period (C), and whole-body thermal conductance (D) in adult male ob/ob mice housed under room temperature conditions [22°C; Baseline: Group 1 (blue), Group 2 (red)] or treated systemically with either veh [Group 1 (blue)] or a physiological dose of T₃ [Group 2 (red)] and subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. 22°C paired Baseline; #P < 0.05 vs. 14°C veh. T₃, triiodothyronine; veh, vehicle.

Fig. 5.

Effect of co-administration of a physiological dose of T₃ and leptin on core body temperature in ob/ob mice during cold exposure. Schematic of study design (A), photoperiod-averaged 24-h core temperature in adult male ob/ob mice housed under room temperature conditions [22°C; Baseline: Group 1 (blue), Group 2 (red); B] or treated systemically with either a physiological replacement dose of T₃ and leptin [T₃-lep, Group 2 (red)] or T₃ alone [T₃-veh, Group 1 (blue)] and subjected to mild cold exposure (14°C; C). Mean change in photoperiod-averaged 24-h core temperature (D) and mean change in core temperature during the dark cycle, light cycle, and 24-h period (E) over all days of treatment in veh-treated mice housed under room temperature conditions (22°C; Baseline) relative to T₃-lep- and T₃-veh-treated mice subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. T₃-veh. lep, leptin; T₃, triiodothyronine; veh, vehicle.

Fig. 6.

Time-course effect during co-administration of a physiological dose of T₃ and leptin on core body temperature and measures of energy homeostasis during cold exposure. Core body temperature (A), heat production (B), ambulatory activity (C), and energy intake (D) in adult male ob/ob mice treated systemically with either a physiological dose of T₃ and leptin administered systemically (T₃-lep) or T₃ alone (T₃-veh) and subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. 14°C T₃-veh. lep, leptin; T₃, triiodothyronine; veh, vehicle.

Fig. 7.

Effect of co-administration of a physiological dose of T₃ and leptin on energy expenditure, respiratory quotient, and ambulatory activity in ob/ob mice during mild cold exposure. Photoperiod-averaged 24-h profiles and mean heat production (A–C), respiratory quotient (RQ; D–F), and ambulatory activity (G–I) during the dark cycle and light cycle, respectively, in adult male ob/ob mice housed under room temperature conditions [22°C; Baseline: Group 1 (blue), Group 2 (red)] or treated systemically with either a physiological dose of T₃ and leptin [T₃-lep, Group 2 (red)] or T₃ alone [T₃-veh, Group 1 (blue)] and subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. 22°C paired Baseline; #P < 0.05 vs. 14°C T₃-veh. lep, leptin; T₃, triiodothyronine; veh, vehicle.

Fig. 8.

Effect of co-administration of a physiological dose of T₃ and leptin on energy intake and thermal conductance in ob/ob mice during mild cold exposure. Photoperiod-averaged 24-h energy intake (A and B), mean energy intake during the dark cycle, light cycle, and 24-h period (C), and whole-body thermal conductance (D) in adult male ob/ob mice housed under room temperature conditions [22°C; Baseline: Group 1 (blue), Group 2 (red)] or treated systemically with either a physiological dose of T₃ and leptin [T₃-lep, Group 2 (red)] or T₃ alone [T₃-veh, Group 1 (blue)] and subjected to mild cold exposure (14°C). n = 7–8 per group. Means ± SE. *P < 0.05 vs. 22°C paired Baseline; #P < 0.05 vs. 14°C T₃-veh. lep, leptin; T₃, triiodothyronine; veh, vehicle.

Fig. 9.

Regulation of body temperature. Conceptual model whereby physiological and behavioral effectors are engaged for controlling body temperature during mild exposure in wild-type mice (A), ob/ob mice (B), and ob/ob mice treated with a physiological dose of leptin or T₃ (C). BAT, brown adipose tissue; T₃, triiodothyronine; WT, wild type.