Diet-induced obese mice retain endogenous leptin action

Abstract

Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice.

Figure 1. Peripheral administration of PLA (3 mg/kg, ip, once daily) in chow fed db/db, ob/ob or lean wildtype control mice

Daily injection of PLA increases energy intake (a), BW (b) and BW change (c) in lean chow-fed control mice but not in mice voided of endogenous leptin signaling. Data shown as mean ± SEM. n=6. *=P<0.05 wt/wt Veh vs. wt/wt PLA; # P<0.05 ob/ob Veh vs. ob/ob PLA. 2-way RM ANOVA, followed by Sidak test.

Figure 2. Peripheral administration of PLA or central infusion of LA in chow fed obese Mc4r-/- or wildtype littermate control male mice

Cumulative energy intake (a,d) BW (b,e) and BW change (c,f) of obese Mc4r-/- mice and wildtype controls receiving either peripheral PLA (3 nmol/kg/day, ip) (a-c) or central infusion of LA (8ug/day, icv) (d-f) for 1-wk. Data shown as mean ± SEM. n=5-8. *=P<0.05 Mc4r^+/+ Veh vs. Mc4r^+/+ treated mice. 2-way RM ANOVA followed by Sidak test.

Figure 3. Peripheral administration of PLA or central infusion of LA in lean and DIO mice

(a-l) Cumulative energy intake (a,d,g,j), BW (b,e,h,k) and BW change (c,f,i,l) of lean and DIO mice receiving either peripheral PLA (1,3,10 nmol/kg/day, ip, a-i) or central infusion of LA (8ug/day, icv) (j-l). (m, n) Change in caloric intake (m) and BW (n) after 6-d of treatment with either peripheral PLA or central LA. (a-l). Data shown as mean ± SEM. n=7-8 (a-i) or n=5 (j-l). *=P<0.05 Lean Veh vs. Lean PLA; #=P<0.05 DIO Veh vs. DIO PLA. 2-way RM ANOVA followed by Sidak test (a-l) or t-Student test (m).

Figure 4. Pomc and Socs3 gene expression and pSTAT3 levels in the arcuate nucleus of mice treated with leptin receptor antagonist

Pomc (a) and Socs3 (b) expression after a single injection of PLA (3mg/kg, ip) in DIO mice 1 h before the onset of the dark phase. Pomc (c) and Socs3 (d) expression after 7-d treatment with PLA (3mg/kg, ip, once daily) on lean and DIO mice. (e,f) p-STAT3 levels relative to beta actin (e) and to total STAT3 (f) measured by inmunoblot in ARC of lean or DIO mice after 7-d infusion with icv LA (8ug/day). Data shown as mean ± SEM. n=5-7; *=P<0.05. (b) t-Student test; (c,d, e). 2-way ANOVA followed by Sidak test.