Steroidogenic Factor 1 in the Ventromedial Nucleus of the Hypothalamus Regulates Age-Dependent Obesity

Abstract

The ventromedial nucleus of the hypothalamus (VMH) is important for the regulation of whole body energy homeostasis and lesions in the VMH are reported to result in massive weight gain. The nuclear receptor steroidogenic factor 1 (SF-1) is a known VMH marker as it is exclusively expressed in the VMH region of the brain. SF-1 plays a critical role not only in the development of VMH but also in its physiological functions. In this study, we generated prenatal VMH-specific SF-1 KO mice and investigated age-dependent energy homeostasis regulation by SF-1. Deletion of SF-1 in the VMH resulted in dysregulated insulin and leptin homeostasis and late onset obesity due to increased food intake under normal chow and high fat diet conditions. In addition, SF-1 ablation was accompanied by a marked reduction in energy expenditure and physical activity and this effect was significantly pronounced in the aged mice. Taken together, our data indicates that SF-1 is a key component in the VMH-mediated regulation of energy homeostasis and implies that SF-1 plays a protective role against metabolic stressors including aging and high fat diet.

4-hydroxy-3-methoxycinnamic acid regulates orexigenic peptides and hepatic glucose homeostasis through phosphorylation of FoxO1

“… 45 In the current study, the FA-treated mice showed resistance to HFD-induced weight gain associated with reduced food intake compared with the vehicle-treated littermates ( Figure 1a–c ). As the hypothalamus has an important role in regulating energy intake, 3 , 4 we investigated whether FA is involved in the regulation of feeding behavior in the hypothalamus. Interestingly, our results show that FA suppressed orexigenic NPY and AgRP expression with no significant effect on the anorexigenic peptides POMC and CART.…”

“… 2 The central nervous system (CNS), particularly the hypothalamus, has an important role in maintaining whole-body energy homeostasis by integrating nutritional signals from peripheral organs and therefore regulates feeding and energy expenditure. 3 , 4 The arcuate nucleus of the hypothalamus consists of two distinct neuronal populations that regulate not only food intake but also energy expenditure and body weight. The orexigenic agouti-related protein (AgRP)- and neuropeptide Y (NPY)-expressing neurons stimulate feeding, whereas the anorexigenic pro-opiomelanocortin (POMC)- and cocaine and amphetamine-regulated transcript (CART)-expressing neurons inhibit food intake and increase energy expenditure.…”

The hypothalamic regulation of metabolic adaptations to exercise

“…Recent studies utilising sophisticated genetic tools show that the main role of the VMH is to regulate energy expenditure and substrate utilisation . The VMH is required for adaptive energy expenditure in response to environmental challenges such as hypoglycaemia, a high‐fat diet (HFD) and ageing . For example, mice with gene specific manipulations in the VMH develop severe obesity and show impaired diet‐induced thermogenesis only when fed a HFD …”

“…26 The VMH is required for adaptive energy expenditure in response to environmental challenges such as hypoglycaemia, 28,29 a high-fat diet (HFD) 30 and ageing. 31,32 For example, mice with gene specific manipulations in the VMH develop severe obesity and show impaired diet-induced thermogenesis only when fed a HFD. 30 Exercise is another metabolic challenge that disrupts homeostasis and this requires the rapid use and mobilisation of energy substrates to satisfy changing energy demands.…”

Insulin Regulates Adrenal Steroidogenesis by Stabilizing SF-1 Activity

“…SF-1 plays an important role in steroid hormones synthesis by regulating the transcription of steroidogenic genes including StAR, Cyp11a1, Cyp17, Cyp11b1, Cyp11b2 and 3β-Hsd 9 , 10 . In addition, SF-1 functions as a metabolic regulator in the brain particularly in the VMH where SF-1 expressing neurons are widespread 11 , 12 .…”