Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice

Abstract

OBJECTIVEAMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin–dependent protein kinase kinase β (CaMKKβ) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.RESEARCH DESIGN AND METHODSMice lacking either Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.RESULTSDeletion of Camkkβ in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte–stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.CONCLUSIONSOur findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

“…It plays a key role in general growth and metabolism of the cells. Deleting the catalytic subunit (ampkα2) from POMC neurons causes obesity and impaired glucose sensing [88, 89]. CaMKK-β is an upstream regulator of AMPK, which is also involved in the regulation of energy homeostasis [65].…”

“…To further examine the role of CaMKK in the hypothalamic control of appetite, Anderson et al ., generated neuron specific CaMKK deletions [65]. Deletion of CaMKK-β in NPY/AgRP neurons reduced food intake and body weight, while deleting CaMKK-β in POMC neurons did not affect energy homeostasis or glucose metabolism [65, 89, 90]. Racioppi et al ., (2012) recently described that genetic ablation of CaMKK2 protected mice from diet-induced obesity, insulin resistance and glucose intolerance.…”

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

“…To further examine the role of CaMKK in the hypothalamic control of appetite, Anderson et al, generated neuron specific CaMKK deletions [65]. Deletion of CaMKK-β in NPY/AgRP neurons reduced food intake and body weight, while deleting CaMKK-β in POMC neurons did not affect energy homeostasis or glucose metabolism [65,89,90]. Racioppi et al, (2012) recently described that genetic ablation of CaMKK2 protected mice from dietinduced obesity, insulin resistance and glucose intolerance.…”

Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity

“…Likewise, deletion of the leptin receptor from POMC neurons disrupts glucose homeostasis but does not affect leptin-mediated anorexia (44). In addition, a variety of POMC neuron–specific KOs have exclusively glucose-related phenotypes (Lkb1 [45], GLP2 [46], S6K [47]). We observed a similarly profound disruption of both glucose tolerance and insulin sensitivity in POMC-λKO mice that was detectable at low levels even within 1 week of HFD feeding in relatively lean mice.…”

“…Similarly, female rodents are more sensitive to the anorexic effects of leptin infusion, whereas males respond more robustly to insulin (53). Deletion of the leptin receptor alone (8) or in combination with the insulin receptor (35), the phosphatidylinositol (3,4,5)-trisphosphate phosphatase Pten (54), the AMPK-regulating kinase Lkb1 (45), and the leptin signaling transcription factor Stat3 (10) all cause obesity in a sex-specific manner. POMC-λKO mice also show sexual dimorphism in their metabolic phenotype: only males have enhanced susceptibility to DIO and disrupted glucose homeostasis.…”