Obesity is associated with increased risk of several chronic diseases and the loss of disease-free years, which has increased the focus of much research for the discovery of therapy to combat it. Under healthy conditions, women tend to store more fat in subcutaneous deposits. However, this sexual dimorphism tends to be lost in the presence of comorbidities, such as type 2 diabetes mellitus (T2DM). Aerobic physical exercise (APE) has been applied in the management of obesity, however, is still necessary to better understand the effects of APE in obese female. Thus, we investigated the effect of APE on body weight, adiposity, exercise tolerance and glucose metabolism in female ob/ob mice. Eight-weeks-old female wild-type C57BL/6J and leptin-deficient ob/ob mice (Lepob) were distributed into three groups: wild-type sedentary group (Wt; n = 6), leptin-deficient sedentary group (LepobS; n = 5) and leptin-deficient trained group (LepobT; n = 8). The LepobT mice were subjected to 8 weeks of aerobic physical exercise (APE) at 60% of the maximum velocity achieved in the running capacity test. The APE had no effect in attenuating body weight gain, and did not reduce subcutaneous and retroperitoneal white adipose tissue (SC-WAT and RP-WAT, respectively) and interscapular brown adipose tissue (iBAT) weights. The APE neither improved glucose intolerance nor insulin resistance in the LepobT group. Also, the APE did not reduce the diameter or the area of RP-WAT adipocytes, but the APE reduced the diameter and the area of SC-WAT adipocytes, which was associated with lower fasting glycemia and islet/pancreas area ratio in the LepobT group. In addition, the APE increased exercise tolerance and this response was also associated with lower fasting glycemia in the LepobT group. In conclusion, starting APE at a later age with a more severe degree of obesity did not attenuate the excessive body weight gain, however the APE promoted benefits that can improve the female health, and for this reason it should be recommended as a non-pharmacological therapy for obesity.

Type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) are among the top ten causes of death in the world. It is observed that the association between T2DM and cardiovascular risk is not the same for both sexes, with cardiovascular risk associated with T2DM being greater in women. Among the different strategies for the prevention and treatment of T2DM and risk factors for CVD, the physical exercise has been largely recommended because of positive effects for the glycemic control, body mass, blood pressure, and lipid profile. Therefore, this manuscript aimed to review the literature about the risk factors that connect T2DM to CVD, the benefits of different types of physical exercise on these factors, and the differences between women and men in this context. The research was carried out in PubMed and Web of Science databases to find works that highlighted the differences between women and men on risk factors that connect T2DM to CVD and the effects of physical exercise. The most recent works, seminal and/or with the closest relationship with T2DM were selected to review. Some different responses were identified between the sexes, although it was not possible to identify whether such differences are due to the characteristics of the sexes or the absence of specific physical exercise protocols for women. In any case, this review reaffirms the benefits of physical exercise for the control of risk factors that connect T2DM and CVD, both in women and in men, and the need for further studies that consider the differences between sexes and so they can propose increasingly adequate protocols.

Aerobic physical training (APT) is an important strategy for prevention and treatment of comorbidities such as type 2 diabetes and obesity. Leptin and adiponectin play an important role in energy metabolism, whose imbalance is strongly related to obesity and insulin resistance (IR). Although women have higher levels of leptin and adiponectin compared to men, in conditions such as obesity and/or type 2 diabetes these levels decrease, abolishing the protective effects of these adipokines in females. This study investigated the effects of APT on the metabolic parameters in leptin‐deficient female mice. For this, 8‐week‐old wild C57BL/J6 (C57) or leptin‐deficient ob/ob (Lepob) female mice were separated into the groups sedentary (S) (C57S, n = 6 and LepobS, n = 5) and trained (T) (LepobT, n = 8). The APT was performed during 1 h/day at 60% of maximal speed achieved in the maximal physical exertion test, 5 times/week for eight weeks. The procedures were approved by the Ethics Committee of the School of Arts, Sciences and Humanities of University of Sao Paulo (#001/2017). LepobS and LepobT groups increased body weight, the weight of retroperitoneal (WAT‐RP) and subcutaneous (WAT‐SC) fat pads compared to C57S. Adipocyte area and diameter of WAT‐RP and WAT‐SC were higher in both LepobS and LepobT compared to C57S, however the APT decreased the WAT‐SC adipocyte area and diameter in LepobT group compared to LepobS. LepobS and LepobT groups showed lower weight of pancreas, gastrocnemius and plantar muscles compared to C57S, however APT prevented the mass reduction of gastrocnemius and plantar muscles in LepobT. Food intake was higher in LepobS compared to C57S, which was counteracted by APT in the LepobT group. The LepobS had fasting hyperglycemia (131 ± 1.02 mg/dL) and glucose intolerance (AUC: 31522 ± 1148 mg/dL/120min) compared to C57S (92 ± 2.51 mg/dL and AUC: 20339 ± 1857 mg/dL/120min). Despite of LepobT group had shown glucose intolerance (AUC: 30085 ± 547 mg/dL/120min), the APT decreased the fasting glycemia (114 ± 6.11 mg/dL) compared to LepobS group. Adiponectin level did not change among groups, as well as the relative area of islets in the pancreatic tissue. During the maximal physical exertion test, LepobT showed higher maximal speed, time to exhaustion and speed on the VO2máx compared to LepobS group. In conclusion, APT prevented the loss of gastrocnemius and plantar muscles mass, reduced WAT‐SC adipocyte hypertrophy and food intake, improved fasting glycemia and aerobic capacity in leptin deficient female mice. Support or Funding Information FAPESP (#2018/22361‐9), CAPES, CNPq

AgradecimentosAgradeço à minha orientadora Anna Karenina, por ser uma das poucas pessoas que acreditaram em mim. Pelo incentivo e aprendizado constantes. Muito obrigada! À minha co-orientadora Fabiana, que não mediu esforços, para o desenvolvimento desse projeto. Muito obrigada! Agradeço minha rede de apoio, familiares, amigos que me ajudaram direta e indiretamente para a realização desse sonho. Através de ajuda com as crianças, com a rotina do dia a dia, financeiramente, ou simplesmente com palavras de conforto nos momentos difíceis. Muito obrigada! Agradeço a duas grandes amigas, Marielza e Flávia, sem elas esse projeto de vida não teria nem começado. Muito obrigada pelo carinho e incentivo sempre! Aos amigos e companheiros de laboratório, Cynthia, Anna Laura, Bruno, Luiz Felipe, Marília, Renatinha, sem dúvidas, esse trabalho seria impossível sem vocês ao meu lado. Muito obrigada! Às técnicas do laboratório de Biomedicina e Biotério da EACH, Lucimara e Isabel, pela disponibilidade e agilidade sempre. Muito obrigada! Aos parceiros do Núcleo de estudos em biociêcias (NEB), Rafael, Luana, Debora, Mayara, Letícia, Fernanda, Flávia, Giovana e Andressa, pelas aulas, debates e conversas que agregam ao meu aprendizado profissional e pessoal. Muito obrigada! Aos parceiros do laboratório de Histologia da Universidade Presbiteriana Mackenzie, ao laboratório de Genética e Cardiologia Molecular do InCor. Muito obrigada! À CAPES pelo apoio financeiro. Muito obrigada! E finalmente, aos meus pais, José Luiz e Vera Lúcia, aos meus irmãos, Tatiana e Leonardo, a meu esposo Álvaro e meus filhos, Victor e Gabriela, que sentiram na pele o que foi toda a trajetória do mestrado em minha vida, e permaneceram sempre ao meu lado. Muito obrigada! Palavras-chaves: Camundongo fêmea Lep ob ; Diabetes tipo 2; Obesidade; Treinamento físico aeróbio. Abstract BOSCHETTI D. Potential of aerobic physical training to minimize the effects of leptin deficiency in an experimental model of female mice. 2019. Thesis (Master's Degree) -Aerobic physical training (APT) has become an important strategy for the prevention and treatment of comorbidities, which may have in common the peripheral resistance to insulin (RI), such as type 2 diabetes and obesity. Characterized by the excessive accumulation of adipose tissue, obesity also implies endocrine dysfunction of this tissue. Leptin and adiponectin are hormones secreted by adipocytes that play an important role in energy metabolism, whose imbalance is strongly related to obesity and RI. Physiologically, women have higher levels of leptin and adiponectin compared to men. However, in conditions such as obesity and/or type 2 diabetes these levels decrease, leaving the body of females without the protective effects of these adipokines. Thus, the present study aimed to investigate the effects of APT on the morphofunctional characteristics of white adipose tissue (WAT) and pancreas in leptin-deficient female mice. For this, 8-week-old wild C57BL/J6 (C57) or leptin-deficient ob/ob (Lep ob ) female mice were separat...