β3-Adrenergic Receptors on White and Brown Adipocytes Mediate β3-Selective Agonist-induced Effects on Energy Expenditure, Insulin Secretion, and Food Intake

Grujić, Danica; Susulic, Vedrana S.; Harper, Mary‐Ellen; Himms‐Hagen, Jean; Cunningham, Barbara A.; Corkey, Barbara E.; Lowell, Bradford B.

doi:10.1074/jbc.272.28.17686

Cited by 224 publications

(178 citation statements)

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“…Mice lacking ␤ 3 receptors had no response to CL316243. Some of the response was restored by expression of ␤ 3 receptors in BAT alone, whereas a robust response was recreated with expression of ␤ 3 receptors in both WAT and BAT (22,29). Our studies ablating WAT and BAT complement the studies of Lowell and colleagues in which WAT and BAT were intact but signaling was ablated.…”

Section: Discussionsupporting

confidence: 63%

See 1 more Smart Citation

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

Гаврилова

Marcus‐Samuels²,

Reitman³

2000

Diabetes

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Stimulation of ␤ 3 -adrenergic receptors increases metabolic rate via lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Other acute effects include decreased gastrointestinal motility and food intake and increased insulin secretion. Chronic treatment with a ␤ 3 agonist ameliorates diabetes and obesity in rodents. We studied the effects of ␤ 3 stimulation in A-ZIP/F-1 mice, which have virtually no WAT, a reduced amount of BAT, severe insulin resistance, and diabetes. In contrast with wild-type mice, treatment of A-ZIP/F-1 mice with CL316243, a ␤ 3 -adrenergic agonist, did not increase O 2 consumption. A single dose of CL316243 produced a 2-fold increase in serum free fatty acids, a 53-fold increase in insulin, and a 2.4-fold decrease in glucose levels in wild-type mice but no change in A-ZIP/F-1 animals. The A-ZIP/F-1 mice also did not show reduced gastrointestinal motility or 24-h food intake during ␤ 3 stimulation. Chronic administration of CL316243 to the A-ZIP/F-1 mice did not improve their thermogenesis, hyperglycemia, or hyperinsulinemia. Thus, all of the ␤ 3 effects studied were absent in the lipoatrophic A-ZIP/F-1 mice, including the effects on nonadipose tissues. From these results, we suggest that all of the effects of ␤ 3 agonists are initiated at the adipocyte with the nonadipose effects being secondary events presumably mediated by signals from adipose tissue. Diabetes 49: [1910][1911][1912][1913][1914][1915][1916] 2000 T he ␤ 3 -adrenergic receptor is a G protein-coupled receptor found predominantly on adipocytes (1-3). ␤ 3 -Adrenergic receptor activity and mRNA have also been reported in the smooth muscle of the gastrointestinal tract and in other sites (2,4,5). ␤ 3 -Adrenergic stimulation causes lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Chronic administration of a ␤ 3 -adrenergic agonist leads to decreased fat mass and improvement of diabetes in rodent obesity models (6,7). Human ␤ 3 research has been hampered by the lack of a sufficiently selective drug (8), but in one study, ␤ 3 -agonist treatment increased nonoxidative glucose disposal and fractional fat oxidation (9). In rodents, acute ␤ 3 -agonist treatment has effects besides stimulating lipolysis and thermogenesis, such as inhibiting gastrointestinal motility and food intake and stimulating insulin secretion. The mechanisms underlying these effects are not well understood.Several transgenic mouse lines with reduced amounts of adipose tissue have been developed (10-13). In the A-ZIP/F-1 mouse, adipose tissue ablation was achieved by adiposeselective expression of a dominant negative protein to certain B-ZIP transcription factors. The A-ZIP/F-1 mice have virtually no WAT, a reduced amount of BAT, leptin deficiency, severe insulin resistance and diabetes, and an accelerated adaptation to fasting (12,14). Surgical transplantation of adipose tissue into A-ZIP/F-1 mice reverses their metabolic syndrome, which demonstrates that the lack of fat is the cause of ...

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Section: Discussionsupporting

confidence: 63%

“…In a complementary approach, Susulic and colleagues (22,29) used mice lacking ␤ 3 -adrenergic receptors and restored ␤ 3 receptors selectively in BAT alone or in both WAT and BAT. Mice lacking ␤ 3 receptors had no response to CL316243.…”

Section: Discussionmentioning

confidence: 99%

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

Гаврилова

Marcus‐Samuels²,

Reitman³

2000

Diabetes

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“…Using knock-out mice the antiobesity effect of 3-AR stimulation has been shown to be through the UCP-1 dependent degradation of fatty acids released from WAT (33,34). Until recently BAT was considered to be restricted to rodents and neonatal humans.…”

Section: Discussionmentioning

confidence: 99%

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Russell

Tisdale

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Objectives:The goal of the current study is to determine whether the -adrenoreceptor (-AR) plays a role in the anti-obesity and anti-diabetic effects of zinc-2-glycoprotein (ZAG). Material and Methods:This has been investigated in CHO-K1 cells transfected with the human 1-, 2-, 3-AR and in ob/ob mice. Cyclic AMP assays were carried out along with binding studies. Ob/ob mice were treated with ZAG and glucose transportation and insulin were examined in the presence or absence of propranonol.Results: ZAG bound to the 3-AR with higher affinity (Kd 46+1nM) than the 2-AR (Kd 71+3nM) while there was no binding to the 1-AR, and this correlated with the increases in cyclic AMP in CHO-K1 cells transfected with the various -AR and treated with ZAG. Treatment of ob/ob mice with ZAG increased protein expression of 3-AR in gastrocnemius muscle, and in white and brown adipose tissue, but had no effect on expression of 1-and 2-AR. A reduction of body weight was seen and urinary glucose excretion, increase in body temperature, reduction in maximal plasma glucose and insulin levels in the oral glucose tolerance test, and stimulation of glucose transport into skeletal muscle and adipose tissue, was completely attenuated by the non-specific -AR antagonist propranolol. Conclusion:The results suggest that the effects of ZAG on body weight and insulin sensitivity in ob/ob mice are manifested through a -3AR, or possibly a 2-AR.

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“…Clenbuterol was ten to thirty times more potent than a β 1 -agonist (dobutamine) or a β 3 -agonist (ICI D-7114) in reducing food intake (Yamashita et al 1994). However, β 3 -agonists do acutely reduce food intake in lean and obese rats (Tsujii & Bray, 1992;Grujic et al 1997) and in lean mice (Susulic et al 1995), but this effect is lost with continued treatment. In mice, knocking out the β 3 adrenergic receptors in white fat blocks the reduction in food intake by β 3 -agonists, indicating that there are peripheral β 3 -adrenergic receptors involved in the modulation of food intake that act on fat cells, and possibly other tissues, to produce inhibitory signals for feeding (Susulic et al 1995).…”

Section: Noradrenaline and Related Compoundsmentioning

confidence: 99%

Afferent signals regulating food intake

2000

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Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. β-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.

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β3-Adrenergic Receptors on White and Brown Adipocytes Mediate β3-Selective Agonist-induced Effects on Energy Expenditure, Insulin Secretion, and Food Intake

Cited by 224 publications

References 35 publications

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Afferent signals regulating food intake

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