TY - JOUR
T1 - Nutrient-sensing hypothalamic TXNIP links nutrient excess to energy imbalance in mice
AU - Schwartz, Gary J.
AU - Blouet, Clemence
PY - 2011/4/20
Y1 - 2011/4/20
N2 - Nutrient excess in obesity and diabetes is emerging as a common putative cause for multiple deleterious effects across diverse cell types, responsible for a variety of metabolic dysfunctions. The hypothalamus is acknowledged as an important regulator of whole-body energy homeostasis, through both detection of nutrient availability and coordination of effectors that determine nutrient intake and utilization, thus preventing cellular and whole-body nutrient excess. However, the mechanisms underlying hypothalamic nutrient detection and its impact on peripheral nutrient utilization remain poorly understood. Recent data suggest a role for thioredoxin-interacting protein (TXNIP) as a molecular nutrient sensor important in the regulation of energy metabolism, but the role of hypothalamic TXNIP in the regulation of energy balance has not been evaluated. Here we show in mice that TXNIP is expressed in nutrient-sensing neurons of the medio basal hypothalamus, responds to hormonal and nutrient signals, and regulates adipose tissue metabolism, fuel partitioning, and glucose homeostasis. Hypothalamic expression of TXNIP is induced by acute nutrient excess and in mouse models of obesity and diabetes, and down regulation of medio basal hypothalamic TXNIP expression prevents diet-induced obesity and insulin resistance. Thus, medio basal hypothalamic TXNIP plays a critical role in nutrient sensing and the regulation of fuel utilization.
AB - Nutrient excess in obesity and diabetes is emerging as a common putative cause for multiple deleterious effects across diverse cell types, responsible for a variety of metabolic dysfunctions. The hypothalamus is acknowledged as an important regulator of whole-body energy homeostasis, through both detection of nutrient availability and coordination of effectors that determine nutrient intake and utilization, thus preventing cellular and whole-body nutrient excess. However, the mechanisms underlying hypothalamic nutrient detection and its impact on peripheral nutrient utilization remain poorly understood. Recent data suggest a role for thioredoxin-interacting protein (TXNIP) as a molecular nutrient sensor important in the regulation of energy metabolism, but the role of hypothalamic TXNIP in the regulation of energy balance has not been evaluated. Here we show in mice that TXNIP is expressed in nutrient-sensing neurons of the medio basal hypothalamus, responds to hormonal and nutrient signals, and regulates adipose tissue metabolism, fuel partitioning, and glucose homeostasis. Hypothalamic expression of TXNIP is induced by acute nutrient excess and in mouse models of obesity and diabetes, and down regulation of medio basal hypothalamic TXNIP expression prevents diet-induced obesity and insulin resistance. Thus, medio basal hypothalamic TXNIP plays a critical role in nutrient sensing and the regulation of fuel utilization.
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U2 - 10.1523/JNEUROSCI.6498-10.2011
DO - 10.1523/JNEUROSCI.6498-10.2011
M3 - Article
C2 - 21508227
AN - SCOPUS:79955754604
SN - 0270-6474
VL - 31
SP - 6019
EP - 6027
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 16
ER -