Title: 17β-Estradiol protects sequestosome 1 deficient mice from hyperphagia and obesity

Speaker: Professor Tetsuro Ishii, University of Tsukuba, Japan

Hosted by:  Section of Vascular Biology & Inflammation, School of Cardiovascular Medicine & Sciences

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].

Notably, we found 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. Female mice, unlike male SQSTM1-KO mice, exhibited a delayed increase in BW with a sharp rise after 25-30 weeks of age. Food intake in female SQSTM1-KO mice also gradually increased after 25-30 weeks. These results suggest that estrogen (17β-estradiol, E₂) 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, and (ii) implanting 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.

Our 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 via different signaling pathways. Supported by Great Britain Sasakawa Foundation

References

1. Harada H, et al. Deficiency of p62/Sequestosome 1 causes hyperphagia due to leptin resistance in the brain. J Neurosci. 2013;33:14767-14677.
2. Gao Q, et al. Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med. 2007;13:89-94.