Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1.

BACKGROUND: Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. METHODS: The MC4Rflox/flox mice with proopiomelanocortin (POMC) -Cre mice were crossed to generate the POMC-MC4Rflox/+ mice. Then POMC-MC4Rflox/+ mice were further mated with MC4Rflox/flox mice to generate the POMC-MC4Rflox/flox mice in which MC4R is selectively deleted in POMC neurons. Bilateral injections of 200 nl of AAV-sh-Kir2.1 (AAV-sh-NC was used as control) were made into the ARC of the hypothalamus. Oxygen consumption, carbon dioxide production, respiratory exchange ratio and energy expenditure were measured by using the CLAMS; Total, visceral and subcutaneous fat was analyzed using micro-CT. Co-immunoprecipitation assays (Co-IP) were used to analyze the interaction between MC4R and Kir2.1 in GT1-7 cells. RESULTS: POMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance. CONCLUSION: Hypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity.

[Breast reconstruction after skin-sparing mastectomy or nipple-sparing mastectomy for breast cancer].

OBJECTIVE: To evaluate the feasibility, oncological safety, and aesthetic result of skin-spring mastectomy (SSM) or nipple-spring mastectomy (NSM) in breast reconstruction of implant (permanent gel or expander) for breast cancer patients who were not fit for the breast conserving surgery (BCS). METHODS: Between October 2005 and July 2011, 89 women with breast caner underwent SSM or NSM, with an average age of 42.4 years (range, 19-55 years) and an average disease duration of 5.7 months (range, 1-24 months). The pathological examination revealed invasive ductal carcinoma in 55 cases, ductal carcinoma in situ (DCIS) in 15 cases, invasive ductal carcinoma + DCIS in 8 cases, DCIS with infiltration in 10 cases, and occult breast cancer in 1 case. According to tumor staging criterion of American Joint Committee on Cancer (AJCC), 15 cases were rated as stage 0, 51 cases as stage I, 22 cases as stage II, and 1 case as unclear. Finally, 33 patients underwent SSM and 56 patients underwent NSM according to the location and diameter of tumor and the infiltration of tumor to nipple. Secondary breast reconstruction was performed with permanent gel replacement after axillary lymph node dissection in 9 patients with positive sentinel lymph node and 1 patient with occult breast cancer; immediate breast reconstruction was performed with permanent gel in the other patients. All the patients received the chemotherapy or/and radiotherapy according to the National Comprehensive Cancer Network (NCCN) guideline. RESULTS: Complications occurred in 5 patients undergoing breast reconstruction of permanent gel after NSM, including 1 case of haemorrhage, 2 cases of infection, and 2 cases of local skin necrosis. Primary healing of incision was obtained in the others. No nipple necrosis was observed in patients undergoing NSM. All the patients were followed up 14-88 months (median, 40 months). At 10 months after operation, the aesthetic results were excellent in 40 cases, good in 33 cases, fair in 14 cases, and poor in 2 cases, with an excellent and good rate of 82%. No recurrence or metastasis was found during follow-up. CONCLUSION: The SSM or NSM is feasible and oncological safe for patients who are not fit for BCS, with satisfactory aesthetic result.