Leptin, a metabolic hormone released from adipose tissue, targets the hypothalamus and plays a key role in the suppression of food intake and body weight gain. We previously reported that a signal modulator sequestosome 1 (SQSTM1), also termed p62/ZIP/A170, positively regulates leptin signaling in mouse brain [1]. An apparent phenotype of SQSTM1 deficient mice is late-onset obesity during feeding a regular chow diet. We concluded that obesity in SQSTM1-KO mice is a consequence of hyperphagia due to defects in brain leptin signaling including STAT3 activation in pro-opiomelanocortin neurons [1]. In this study, we examined differences in the kinetics of age-dependent body weight (BW) gain between male and female SQSTM1-KO C57BL mice during feeding a standard chow diet. All experiments were conducted according to the guidelines of the Animal Experiment Committee in the University of Tsukuba. Female mice, unlike male SQSTM1-KO mice, exhibited a delayed increase in BW with a sharp rise after 25-30 weeks of age and their mean BWs compared to wild type female mice at 30 and 50 weeks were respectively 117 and 207% (n=5). Food intake in female SQSTM1-KO mice also gradually increased after 25-30 weeks. These results suggest that estrogen may protect against the deficits in leptin signaling in young female SQSTM1-KO mice, as estrogen is associated with anorectic effects similar to leptin [2]. This hypothesis is confirmed by the following results: (i) ovariectomy of SQSTM1-KO mice at 10 weeks of age induces about 20% increase in food intake and greater BW gain relative to control KO mice with BW changes in over the next 10 weeks increasing respectively from 18.9±2.7 to 28.9±2.7 and 19.3±1.6 to 24.0±3.3 (g, n=7, P<0.01, Student t-test) for ovariectomized and control sham operated mice, and (ii) implanting 17β-estradiol (E2) releasing tablets to maintain physiological levels of E2 for several weeks in male SQSTM1-KO mice at 12 weeks of age induces suppression of food intake by about 20% and largely inhibited BW gain, with BW gain over the next 6 weeks increasing respectively from 30.1±2.1 to 30.6±2.3 and 30.6±1.6 to 34.8±3.8 (g, n=6) for the E2 tablet and placebo treated male SQSTM1-KO mice. These results suggest that E2 compensates for deficits in leptin signaling in both male and female SQSTM1-KO mice. Interestingly, Gao et al. [2] reported that E2 induces STAT3 activation in POMC neurons in the arcuate nucleus in both leptin-deficient and leptin receptor-deficient mice. Their study and our results suggest that SQSTM1 plays a role in sensitising the leptin-receptor signaling while estrogen-mediated signaling bypasses the leptin-receptor pathway allowing activation of leptin-like effects including STAT3 activation via different signaling pathways. Further studies are required to uncover the mechanisms underlying SQSTM1 involvement in leptin signaling including STAT3 activation in the brain.