The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis

Abstract

Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr(flox/flox) mice) and their controls with normal Lepr (Lepr(flox/flox) mice). Pomc-Cre, Lepr(flox/flox) mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc-Cre, Lepr(flox/flox) females accumulated more fat than OVX Lepr(flox/flox) females did. Pomc-Cre, Lepr(flox/flox) males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr(flox/flox) females had similar glucose tolerance before and after OVX. Therefore leptin's action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones.

Figure 1

Circulating estradiol levels (A) and hypothalamic ER α mRNA levels (B) of sham-operated (sham) or ovariectomized (OVX) mice. * denotes significant difference from sham female Lepr^flox/flox mice (P < 0.05). † denotes significant difference from sham female Pomc-Cre, Lepr^flox/flox mice (P < 0.05).

Figure 2

Total body fat change (A), carcass (B) and subcutaneous (C) fat, carcass (D) and subcutaneous (E) fat % of male and female mice before and after surgeries. * denotes difference between genotypes within same sex procedure (e.g., Lepr^flox/flox vs. Pomc-Cre, Lepr^flox/flox within Female Sham). † denotes difference between sex procedure within genotype (e.g., Male Sham vs. Female Sham vs. Female OVX within Lepr^flox/flox). P < 0.05.

Figure 3

ipGTT of pre-sham (A) and post-sham (B) males, pre-sham (C) and post-sham (D) females, and pre-OVX (E) and post-OVX females (F). * denotes significant difference between genotypes (P < 0.05).