Leptin Action in the Dorsomedial Hypothalamus Increases Sympathetic Tone to Brown Adipose Tissue in Spite of Systemic Leptin Resistance

Enriori, Pablo J.; Sinnayah, Puspha; Simonds, Stephanie E.; Rudaz, Cecilia Garcia; Cowley, Michael A.

doi:10.1523/jneurosci.2336-11.2011

Cited by 263 publications

(283 citation statements)

References 46 publications

Supporting

Mentioning

250

Contrasting

Unclassified

Order By: Relevance

“…For instance, induction of leptin resistance in the presence of obesity induces an increase in endocannabinoid tone (Scherer & Buettner 2009, Bermudez-Silva et al 2012, which could lead to the suppression of CRH. However, leptin resistance induced by high fat feeding is selective and does not impact on autonomic nervous system activity (Enriori et al 2011). Thus, it could be speculated that hyperleptinemia dampens CRH expression and release in the face of selective sensitivity of the central HPA axis.…”

Section: Discussionmentioning

confidence: 99%

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

Auvinen

Romijn²,

Biermasz³

et al. 2012

Journal of Endocrinology

View full text Add to dashboard Cite

Alterations in hypothalamus-pituitary-adrenal (HPA) axis activity have been linked to the development of the metabolic syndrome (MetS). Common features of the MetS, like insulin resistance and obesity, are reproducibly induced by high fat diet (HFD) in animal models of diet-induced obesity. These models, hampered by methodological differences, reveal conflicting results with respect to HPA axis activation. This study was aimed to evaluate in detail nonstressed diurnal HPA axis activity in mice during obesity development. Male C57Bl/6J mice were fed high or low fat diet for 12 weeks.

show abstract

Section: Discussionmentioning

confidence: 99%

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

Auvinen

Romijn²,

Biermasz³

et al. 2012

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…They have higher leptin levels, but they have higher peripheral resistance to the actions of this protein instead [20]. Leptin is secreted by adipocytes and has several physiological roles that include increasing activity of the sympathetic nervous system, which stimulates energy expenditure in brown adipose tissue and increases metabolic rate and, therefore, body heat [21]. Thus, obese patients exhibit less heat redistribution from core to peripheral tissue after anaesthetic induction [10].…”

Section: Discussionmentioning

confidence: 99%

Comparison of peri‐operative core temperature in obese and non‐obese patients*

et al. 2012

View full text Add to dashboard Cite

SummaryOur aim was to compare peri-operative core temperatures and the incidence of hypothermia in obese and non-obese women with active forced-air warming. Twenty female patients scheduled for abdominal surgery were allocated to two groups according to body mass index. Ten obese (30.0-34.9 kg.m )2) and 10 non-obese (18.5-24.9 kg.m ) women received forced-air warming on their lower limbs. At the end of surgery, the mean (SD) core temperatures were 36.7 (0.5)°C in the obese group and 36.0 (0.6)°C in the non-obese group (p < 0.001). Only in the non-obese group was there a significant decrease in the intra-operative core temperature values (p < 0.001). The incidences of intra-operative hypothermia were lower in the obese group (10%) compared with non-obese group (60%; p = 0.019). In the postoperative recovery phase, the mean (SD) core temperature data were higher in the obese group than in the nonobese group (36.2 (0.4) vs 35.6 (0.5)°C, respectively (p < 0.001)). In conclusion, obese female patients have higher perioperative core temperature and a lower incidence of hypothermia compared with non-obese female patients during abdominal surgery with active forced-air warming. Accepted: 21 August 2012Unintentional peri-operative hypothermia (core temperatures between 34.5 and 35.9°C) often leads to adverse outcomes, including cardiac events secondary to sympathetic nervous system activation [1], surgicalwound infections and prolonged hospitalisation [2], coagulopathy and increased blood loss [3], impaired drug metabolism, delayed postoperative recovery period [4,5] and shivering [6]. Therefore, maintaining perioperative normothermia reduces morbidity [1][2][3] and the use of peri-operative warming devices has become routine.The prevalence of obesity has increased markedly worldwide in recent years [7]. In clinical practice, body mass index (BMI) is used to estimate the degree of obesity, which is classified in three levels: grade 1 (BMI from 30.0 to 34.9 kg.m ) [8]. The prevalence of grade-1 obesity is higher among both female and male obese populations than are the other grades [8]. Obese patients are more likely to vasoconstrict in cooler environments [9], have reduced heat redistribution from core to peripheral tissue after

show abstract

“…In addition, activation of leptin signaling in the VMH induces activation of the sympathetic nervous system (SNS) and increased UCP1 expression in iBAT (25)(26)(27). UCP1 is well known to be a key regulator of thermogenesis in iBAT (28).…”

Section: Introductionmentioning

confidence: 99%

“…The VMH is a key site for leptin action, and the activation of leptin signaling in the VMH, including SF-1 neurons, regulates energy homeostasis and SNS activation (2,12,15,23,24,26,27). FOXO1 acts as a negative regulator of leptin action in the hypothalamus (2,7,8).…”

Section: Introductionmentioning

confidence: 99%

FOXO1 in the ventromedial hypothalamus regulates energy balance

Kim¹,

Donato²,

Berglund³

et al. 2012

J. Clin. Invest.

126

108

View full text Add to dashboard Cite

The transcription factor FOXO1 plays a central role in metabolic homeostasis by regulating leptin and insulin activity in many cell types, including neurons. However, the neurons mediating these effects and the identity of the molecular targets through which FOXO1 regulates metabolism remain to be defined. Here, we show that the ventral medial nucleus of the hypothalamus (VMH) is a key site of FOXO1 action. We found that mice lacking FOXO1 in steroidogenic factor 1 (SF-1) neurons of the VMH are lean due to increased energy expenditure. The mice also failed to appropriately suppress energy expenditure in response to fasting. Furthermore, these mice displayed improved glucose tolerance due to increased insulin sensitivity in skeletal muscle and heart. Gene expression profiling and sequence analysis revealed several pathways regulated by FOXO1. In addition, we identified the nuclear receptor SF-1 as a direct FOXO1 transcriptional target in the VMH. Collectively, our data suggest that the transcriptional networks modulated by FOXO1 in VMH neurons are key components in the regulation of energy balance and glucose homeostasis. IntroductionDefective regulation of energy balance results in obesity and components of metabolic syndrome, such as type 2 diabetes. Understanding the molecular and cellular mechanisms underlying the ability of the central nervous system to regulate energy balance and glucose homeostasis is an area of active investigation. Many proteins are involved in the modulation of metabolic homeostasis. This includes the transcription factor FOXO1, which has been demonstrated to regulate leptin and insulin action in the brain (1, 2). The biological significance of mammalian FOXO1 was initially reported in studies in Caenorhabditis elegans. Two independent groups identified Daf-16 (a homolog of the mammalian FOXO1) as a negative regulator of Daf2 (a homolog of the mammalian insulin receptor) signaling in C. elegans, implying that FOXO1 may play important roles in insulin signaling (3, 4). Subsequent studies using mouse models have confirmed the functional significance of FOXO1 as a critical mediator of insulin effects in many mammalian peripheral cells (1,5,6).Recently, critical metabolic roles of FOXO1 in the hypothalamus have been reported (2, 7). Both studies assessed the role of FOXO1 in melanocortin neurons in the arcuate nucleus of the hypothalamus (ARH). Specifically, they reported POMC and Agrp genes as direct targets of FOXO1. A subsequent report using POMC-specific FOXO1 KO mice demonstrated that FOXO1 plays important roles in regulation of food intake, body weight, and leptin sensitivity, partially depending on the expression of carboxypeptidase E (Cpe) (8). Furthermore, analyses of PDK1/FOXO1 pathways revealed critical roles of FOXO1 to control food intake, body length, and body weight in AGRP neurons of hypothalamus (9).FOXO1 is also highly expressed in many other hypothalamic nuclei, including the dorsomedial nucleus of the hypothalamus and the ventral medial nucleus of the hypothalamus (VMH) ...

show abstract

Leptin Action in the Dorsomedial Hypothalamus Increases Sympathetic Tone to Brown Adipose Tissue in Spite of Systemic Leptin Resistance

Cited by 263 publications

References 46 publications

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

Comparison of peri‐operative core temperature in obese and non‐obese patients*

FOXO1 in the ventromedial hypothalamus regulates energy balance

Contact Info

Product

Resources

About