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| Author(s): |
Aline Alves de Jesus
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2023-10-11 |
| Examining board members: |
Lucila Leico Kagohara Elias;
Luiz Osório Silveira Leiria;
Luiz Carlos Carvalho Navegantes;
Lício Augusto Velloso
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| Advisor: | Lucila Leico Kagohara Elias |
| Abstract | |
Obesity occurs due to an imbalance between food intake and caloric expenditure and affects millions of people around the world, being linked to an increased risk for the development of heart disease, diabetes mellitus and metabolic syndrome. Women at the end of their reproductive life (menopause) are at greater risk of developing obesity when compared to men. Several studies have shown that this event occurs due to a decrease in the production of the ovarian hormone 17β estradiol (E2) during menopause, which plays an important role in the control of energy homeostasis. The hypothalamus, the main regulator to promote energy homeostasis , receives hormonal signals, such as E2 and nutrients, from the peripheral system that act on neurons in the arcuate nucleus (ARC), which express pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART), neuropeptides that promote anorexigenic effects (reduce food intake and induce satiety), and another population of neurons that express neuropeptide Y (NPY) and Agouti protein (AgRP), orexigenic neuropeptides (stimulate appetite). Stimulation of POMC neurons, in turn, induces firing of neurons in second-order nuclei, such as neurons expressing steroidogenic factor 1 (SF1) in the ventromedial hypothalamic nucleus (VMH), which in turn regulate food intake and energy expenditure attenuating the diet induced obesity (DIO). However, little is known about the intracellular mechanisms by which VMH neurons mediate these effects. Thus, this study aimed to investigate the role of phosphatidylinositol kinase 3 (PI3K) signaling in SF1 neurons of the VMH in the control of energy homeostasis, as well as the participation of this pathway in the effects of E2 on body weight regulation. The Cre-lox methodology was used to generate mice with specific deletion of the P110α catalytic subunit in SF1 neurons, which allowed us to generate SF1-cre;P110αflox/flox (experimental) and P110αflox/flox (control) mice. Body weight, food intake, indirect calorimetry, thermogenesis, glycemic metabolism, serum insulin and leptin concentrations were evaluated in experimental animals and controls of both sexes, treated with a regular (RD) or high-fat (HFD) diet. Females underwent ovariectomy (OVX) and subcutaneous implantation of E2 pellets for the assessment of body weight, food intake, energy expenditure and thermogenesis. We demonstrated that the conditional deletion of P110α in VMH SF1 neurons (SF1-cre;P110α flox/flox) reduced O2 consumption and energy expenditure in male mice under a regular diet. However, the reduction of PI3K activity in the VMH did not affect body weight, food intake, glucose and insulin tolerance. In female SF1-cre;P110α flox/flox mice, an increase in cumulative food intake was observed, but there was no change in body weight, indirect calorimetry, and glucose and insulin tolerance. When challenged with HFD, disruption of PI3K in SF1 neurons caused a significant increase in body weight that was more relevant in females without changing food intake. In both sexes, a reduction in insulin tolerance, energy expenditure and thermogenesis were observed. The conditional knockout of the P110α subunit in the VMH partially reduced the effects of 17β-estradiol in OVX females on body weight control, stimulation of energy expenditure and sympathetic activity and BAT thermogenesis. Collectively, our results indicate that PI3K activity in VMH SF1 neurons plays a relevant role to protect against diet-induced obesity (DIO) and participates in the actions of E2 in regulating energy homeostasis in female mice. (AU) | |
| FAPESP's process: | 20/07368-7 - PI3K role in the effects of estradiol on SF-1 neurons in the control of energy homeostasis |
| Grantee: | Aline Alves de Jesus |
| Support Opportunities: | Scholarships in Brazil - Doctorate |