To examine the role of AMP-activated protein kinase (AMPK) in muscle glucose transport, we generated muscle-specific transgenic mice (TG) carrying cDNAs of inactive ␣2 (␣2i TG) and ␣1 (␣1i TG) catalytic subunits. Extensor digitorum longus (EDL) muscles from wild type and TG mice were isolated and subjected to a series of in vitro incubation experiments. In ␣2i TG mice basal ␣2 activity was barely detectable, whereas basal ␣1 activity was only partially reduced. Known AMPK stimuli including 5-aminoimidazole-4-carboxamide-1-␤-4-ribofuranoside (AICAR), rotenone (a Complex I inhibitor), dinitrophenol (a mitochondrial uncoupler), muscle contraction, and sorbitol (producing hyperosmolar shock) did not increase AMPK ␣2 activity in ␣2i TG mice, whereas ␣1 activation was attenuated by only 30 -50%. Glucose transport was measured in vitro using isolated EDL muscles from ␣2i TG mice. AICAR-and rotenone-stimulated glucose transport was fully inhibited in ␣2i TG mice; however, the lack of AMPK ␣2 activity had no effect on contraction-or sorbitol-induced glucose transport. Similar to these observations in vitro, contraction-stimulated glucose transport, assessed in vivo by 2-deoxy-D-[ 3 H]glucose incorporation into EDL, tibialis anterior, and gastrocnemius muscles, was normal in ␣2i TG mice. Thus, AMPK ␣2 activation is essential for some, but not all, insulin-independent glucose transport. Muscle contraction-and hyperosmolarity-induced glucose transport may be regulated by a redundant mechanism in which AMPK ␣2 is one of multiple signaling pathways.Recent reports suggest that AMP-activated protein kinase (AMPK), 2 a member of a metabolite-sensing protein kinase family, controls blood glucose homeostasis by regulating glucose transport in skeletal muscle and glucose production in the liver (1, 2). In skeletal muscle activation of AMPK by pharmacological stimulation and transient expression of an AMPK-active mutant increases glucose transport (3-6). AMPK also seems to play a role in enhancing muscle (7) and whole body (8) insulin sensitivity and responsiveness for glucose transport. Because skeletal muscle accounts for ϳ80% of disposal of an oral glucose load (9, 10) and because type 2 diabetes is associated with reduced muscle glucose disposal (11), AMPK may be critical in the control of metabolic homeostasis and perhaps the development of type 2 diabetes (12, 13). Not surprisingly, AMPK is now considered a drug target for the treatment of type 2 diabetes (14).AMPK is a serine/threonine kinase consisting of a catalytic ␣ subunit and regulatory ␤ and ␥ subunits (15-17). Different isoforms have been reported for each subunit (␣1 and ␣2, ␤1 and ␤2, ␥1, ␥2, and ␥3) with tissue-specific distribution. In skeletal muscle, ␣2 (18, 19), ␤2 (20, 21), and ␥1 (18) or ␥3 (22) are the major isoforms expressed and form the majority of AMPK heterotrimer complexes. AMPK is activated in response to decreases in intracellular ATP and concomitant increases in AMP, increasing the AMP:ATP ratio (15-17).It has long been believed that there are two m...

Leptin activates the long form of the leptin receptor (LRb) to control feeding and neuroendocrine function and thus regulate adiposity. While adiposity influences insulin sensitivity, leptin also regulates glucose homeostasis independently of energy balance. Disruption of the LRb/STAT3 signal in s/s mice results in hyperphagia, neuroendocrine dysfunction, and obesity similar to LRb null db/db mice. Insulin resistance and glucose intolerance are improved in s/s compared to db/db animals, however, suggesting that LRb/STAT3-independent signals may contribute to the regulation of glucose homeostasis by leptin. Indeed, caloric restriction normalized glycemic control in s/s animals, but db/db mice of similar weight and adiposity remained hyperglycemic. These differences in glucose homeostasis were not attributable to differences in insulin production between s/s and db/db animals but rather to decreased insulin resistance in s/s mice. Thus, in addition to LRb/STAT3-mediated adiposity signals, non-LRb/STAT3 leptin signals mediate an important adiposity-independent role in promoting glycemic control.