Passage
Leptin signaling is vital for maintaining adequate body mass and preventing insulin resistance. When energy stores are abundant, adipocytes produce leptin to stimulate fatty acid oxidation and glucose utilization. One result of leptin signaling in skeletal muscle cells is the phosphorylation and activation of adenosine monophosphate-activated protein kinase (AMPK) . AMPK facilitates the breakdown of triglycerides by decreasing the activity of acetyl-coenzyme A carboxylase (ACC) ; this leads to downregulation of fatty acid synthesis and upregulation of β-oxidation.Fatty acid oxidation has been studied by analyzing the effect of leptin on activation of AMPK and ACC in soleus muscles. To identify leptin's mode of action, injections were administered to transgenic mice via the intravenous (1 mg/kg i.v.) and intrahypothalamic (1 ng i.h.p [faster drug delivery]) routes. Phentolamine (PH) , an α-adrenergic receptor ligand that binds to the same receptor as leptin, was administered concurrently in some of the mice. Signaling to ACC from the citric acid cycle was also examined through the addition of citrate.
Figure 1 AMPK activity measured in soleus muscle injected with leptin and PH via i.v. and i.h.p.Table 1 ACC Activity in Soleus Muscle Exposed to Leptin Delivered via i.v. and i.h.p Injections in vivo
Adapted from Minokoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415(6869) :339-43.
-What best describes the action of PH on AMPK activity?

Question

Passage
Leptin signaling is vital for maintaining adequate body mass and preventing insulin resistance. When energy stores are abundant, adipocytes produce leptin to stimulate fatty acid oxidation and glucose utilization. One result of leptin signaling in skeletal muscle cells is the phosphorylation and activation of adenosine monophosphate-activated protein kinase (AMPK) . AMPK facilitates the breakdown of triglycerides by decreasing the activity of acetyl-coenzyme A carboxylase (ACC) ; this leads to downregulation of fatty acid synthesis and upregulation of β-oxidation.Fatty acid oxidation has been studied by analyzing the effect of leptin on activation of AMPK and ACC in soleus muscles. To identify leptin's mode of action, injections were administered to transgenic mice via the intravenous (1 mg/kg i.v.) and intrahypothalamic (1 ng i.h.p [faster drug delivery]) routes. Phentolamine (PH) , an α-adrenergic receptor ligand that binds to the same receptor as leptin, was administered concurrently in some of the mice. Signaling to ACC from the citric acid cycle was also examined through the addition of citrate.

Figure 1 AMPK activity measured in soleus muscle injected with leptin and PH via i.v. and i.h.p.Table 1 ACC Activity in Soleus Muscle Exposed to Leptin Delivered via i.v. and i.h.p Injections in vivo

Adapted from Minokoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415(6869) :339-43.
-What best describes the action of PH on AMPK activity?

Quizplus · Accepted Answer

11ecba2d_0dc4_8435_a3bf_e7bbe19ea4e4_MD0008_00 In the study described in the passage, the control (baseline) was established as normal AMPK activity (at 100%). The activity of AMPK was assessed when PH was present or absent during leptin exposure (i.v. and i.h.p. at various time points). Muscles exposed to leptin only (no PH) showed a substantial increase in AMPK activity at i.v. 0.5 hr, i.v. 6 hr, and i.h.p. 1 hr. However, AMPK activity decreased in muscles exposed to both PH and leptin at i.v. 6 hr and i.h.p. 1 hr (due to faster drug delivery). This result signified that PH was blocking the leptin receptor and preventing AMPK activity from being increased by leptin, causing AMPK activity to return to a value close to baseline. PH can therefore be an antagonist, a compound that alters receptor-ligand binding affinity or binds a receptor directly to decrease the cell's response to the ligand. In addition, the increased amount of time taken for PH to lower AMPK activity (ie, inactive at 0.5 hr but active at i.v. 6 hr and 1 hr i.h.p) suggests that PH acts in a time-dependent manner. (Choices A and D) An agonist enhances or duplicates the effect of a ligand binding to a receptor. For PH to act as an agonist, it would have to bind to leptin-specific receptors and induce a biochemical response similar to that of leptin (ie, increase AMPK activity). (Choice B) AMPK activity was still increasing at i.v. 0.5 hr due to leptin exposure in the presence of PH. This increase implies that PH does not act immediately, which is supported by the fact that AMPK activity returned to a value close to baseline only with leptin (plus PH) at i.v. 6 hr. Educational objective: An agonist enhances or duplicates the effect of a ligand binding to a receptor. Antagonists alter receptor-ligand binding affinity or bind directly to a receptor to decrease the cell's response to the ligand. The effect of agonists or antagonists can be time-dependent (ie, may not be immediate).

Passage Leptin Signaling Is Vital for Maintaining Adequate Body Mass and and Preventing