RESUMO
Testosterone (T) reduces male fat mass, but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high-fat diet-induced adult obese male mice to supplementation with T or the nonaromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed the absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. The stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by the stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Receptor alfa de Estrogênio/fisiologia , Atividade Motora/fisiologia , Testosterona/farmacologia , Tecido Adiposo/metabolismo , Animais , Di-Hidrotestosterona/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Hipogonadismo/genética , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Atividade Motora/efeitos dos fármacos , Obesidade/genética , Obesidade/metabolismo , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Congêneres da Testosterona/farmacologiaRESUMO
The mismatch between maternal undernutrition and adequate nutrition after birth increases the risk of developing metabolic diseases. We aimed to investigate whether the hyperghrelinemia during maternal undernourishment rewires the hypothalamic development of the offspring and contributes to the conversion to an obese phenotype when fed a high-fat diet (HFD). Pregnant C57BL/6 J, wild type (WT) and ghrelin receptor (GHSR)-/- mice were assigned to either a normal nourished (NN) group, or an undernutrition (UN) (30% food restricted) group. All pups were fostered by NN Swiss mice. After weaning, pups were fed a normal diet, followed by a HFD from week 9. Plasma ghrelin levels peaked at postnatal day 15 (P15) in both C57BL/6 J UN and NN pups. Hypothalamic Ghsr mRNA expression was upregulated at P15 in UN pups compared to NN pups and inhibited agouti-related peptide (AgRP) projections. Adequate lactation increased body weight of UN WT but not of GHSR-/- pups compared to NN littermates. After weaning with a HFD, body weight and food intake was higher in WT UN pups but lower in GHSR-/- UN pups than in NN controls. The GHSR prevented a decrease in ambulatory activity and oxygen consumption in UN offspring during ad libitum feeding. Maternal undernutrition triggers developmental changes in the hypothalamus in utero which were further affected by adequate feeding after birth during the postnatal period by affecting GHSR signaling. The GHSR contributes to the hyperphagia and the increase in body weight when maternal undernutrition is followed by an obesity prone life environment.
Assuntos
Hipotálamo/metabolismo , Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/metabolismo , Receptores de Grelina/metabolismo , Animais , Animais Recém-Nascidos , Dieta Hiperlipídica/efeitos adversos , Feminino , Deleção de Genes , Hipotálamo/crescimento & desenvolvimento , Masculino , Desnutrição/complicações , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Gravidez , Receptores de Grelina/genéticaRESUMO
Roux-en-Y gastric bypass (RYGB) is thought to reduce calcium absorption from the gut. Here, we report the case of a patient with a RYGB, who developed primary hypoparathyroidism after a total thyroidectomy, leading to recalcitrant hypocalcaemia. Despite aggressive oral calcium and calcitriol supplementation, she remained hypocalcaemic and required intravenous (IV) calcium supplementation to control her symptoms, and to keep calcium serum levels within an acceptable range. Teriparatide treatment improved calcium levels marginally. This treatment, however, was poorly tolerated and ultimately stopped by the patient. As a last resort, reversal of RYGB was performed to improve calcium absorption from the gut. Unfortunately, IV calcium supplementation remained necessary. This case illustrates that the reversal of RYGB is not always a guarantee for success in managing recalcitrant hypocalcaemia.
Assuntos
Derivação Gástrica , Hipocalcemia , Hipoparatireoidismo , Obesidade Mórbida , Feminino , Humanos , Hipocalcemia/tratamento farmacológico , Hipocalcemia/etiologia , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/etiologia , Obesidade Mórbida/cirurgia , TireoidectomiaRESUMO
BACKGROUND: Bone loss and increased fracture risk following bariatric surgery has been reported. We investigated whether the two most commonly performed surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), lead to bone loss. In addition, we examined whether fortification of the diet with calcium citrate prevents bone loss. METHODS: We used mouse models for SG and RYGB and compared bone loss with a group of sham mice with similar weight loss. All groups were switched at the time of surgery to a low-fat diet (LFD). We also examined whether fortification of the diet with calcium citrate and vitamin D was able to prevent bone loss. RESULTS: At 2 weeks we observed no major bone effects. However, at 8 weeks, both trabecular and cortical bone were lost to the same extent after SG and RYGB, despite increased calcium absorption and adequate serum levels of calcium, vitamin D, and parathyroid hormone (PTH). Diet fortification with calcium citrate and vitamin D was able to partially prevent bone loss. CONCLUSIONS: Both SG and RYGB lead to excess bone loss, despite intestinal adaptations to increase calcium absorption. Fortifying the diet with calcium citrate and vitamin D partly prevented the observed bone loss. This finding emphasizes the importance of nutritional support strategies after bariatric surgery, but also affirms that the exact mechanisms leading to bone loss after bariatric surgery remain elusive and thus warrant further research.