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U.S.-Japan Biomedical Research Laboratories, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
Address all correspondence and requests for reprints to: Akira Arimura, M.D., Ph.D., U.S.-Japan Biomedical Research Laboratory, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, Box SL-21, New Orleans, Louisiana 70112. E-mail: Arimura{at}tulane.edu.
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Introduction |
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Three laboratories (3, 4, 5) have prepared PACAP knockout mice, and two groups have reported a high mortality during early ages. The Sherwood group (3) previously reported that most of the homozygous PACAP null mice died within the first 2 wk after birth in a wasted state with lipid droplets in the liver, heart, and skeletal muscle cells. The same group reported in this issue of Endocrinology (6) that the premature death of the PACAP-deficient mice that occurred when the animals were raised at 21 C resulted from impaired adaptive thermogenesis. When these animals were raised at an environmental temperature of 21 C, only 11% of the PACAP-deficient mice survived past the first 2 wk. The premature death of PACAP null mice was prevented when these animals were raised at an environmental temperature of 24 C. At this temperature, 76% of the PACAP-deficient mice survived. Furthermore, when the 7-d-old mice were separated from the mother and placed at 21 C, the PACAP null mice showed a greater loss of core body temperature compared with the wild-type mice, indicating an impaired thermal adaptation in the PACAP-deficient animals.
Thermogenesis in response to cold stress takes place by two different mechanisms: adaptive thermogenesis that occurs in the brown adipose tissues and shivering thermogenesis in the skeletal muscles. In the neonate and small rodents, adaptive thermogenesis that takes place in the brown adipose tissues plays a major role in the production of heat in a cold environment. On the other hand, in large animals including adult humans, shivering thermogenesis is the major mechanism of heat production. Adaptive thermogenesis is mediated by norepinephrine, which is released from the sympathetic nerve endings distributed in the brown adipocytes and the blood vessels in the brown adipose tissues (7). The importance of norepinephrine and epinephrine in thermogenesis is supported by the finding that mice deficient in dopamine ß-hydroxylase, the enzyme that catalyzes the conversion of dopamine to norepinephrine, are highly cold sensitive (8). In the brown adipose tissue, norepinephrine released by the nerve endings binds to the ß-adrenergic receptors of brown adipocytes and activates hormone-sensitive (HS) lipase and uncoupling protein 1 (UCP1). Activated HS lipase catalyzes the breakdown of stored triglycerides into free fatty acids, which then enter the mitochondria. UCP1 is the only protein that can uncouple respiration from ATP formation and release energy in the form of heat. UCP1-deficient animals are also intolerant to the cold (9).
Gray et al. (6) observed that the levels of norepinephrine and its precursor, dopamine, in the brown adipose tissues of the PACAP null mice were significantly lower than those in the control mice. Neither the mass nor the histology of the interscapular brown adipose tissues of PACAP-deficient mice differed from those in the wild-type mice. On the other hand, the levels of the mRNAs for both HS lipase and UCP1 in the brown adipose tissues were increased by 1.6-fold. Although tyrosine hydroxylase (TH) mRNA levels in the brown adipose tissues were not reported, the levels of TH mRNA in the adrenal medulla of the PACAP null mice were two times greater than those in the heterozygous and wild-type controls. On the other hand, the levels of epinephrine and norepinephrine in the adrenal medulla in PACAP-deficient mice did not differ from those in the heterozygous and wild-type mice. The increased levels of TH mRNA in the adrenal medulla could reflect a compensatory response designed to restore the lowered levels of catecholamines in these tissues. Neither norepinephrine nor epinephrine levels in the plasma differed among the three genotypes. On the other hand, dopamine levels in the plasma of PACAP null mice and heterozygous mice were lower than those in the wild-type mice. Although the reason for the lowered plasma dopamine level was not reported in this study, it is possible that TH activity in the tissues or organs that are a major source for circulating dopamine, including the stomach (10), could be altered in PACAP null mice. Although PACAP may stimulate the expression of TH, dopamine ß-hydroxylase, and phenylethanolamine-N-methyltransferase (11), the peptide may not necessarily play an obligatory role in the transcription of their mRNAs. In the adrenal medulla of PACAP-deficient mice, the TH mRNA levels were increased compared with those in the control mice. More importantly, PACAP may play a critical role in activation (phosphorylation) of TH (12). Unfortunately, the present paper does not report the levels of phosphorylated TH in the brown adipose tissues and adrenal medulla of PACAP null mice, the amount of TH activity, or, more important, the turnover rate of norepinephrine in brown adipose tissues.
PACAP binds to not only the PACAP-specific receptor, PAC1 receptor, but also to two types of VIP receptors, called VPAC1 receptors and VPAC2 receptors, with the same or even a higher affinity than VIP (1). On the other hand, VIP binds to PAC1 receptors with an affinity 1000 times lower than PACAP. The impaired adaptive thermogenesis in the PACAP null mice, in which the expression of VIP may be unaffected, suggests that the effect of PACAP is not mediated by VPAC1 receptors or VPAC2 receptors, but by PAC1 receptors. The premature death of PAC1-receptor-deficient mice has also been observed. The rate of premature death of the PAC1-receptor-deficient mice is approximately 50–70% before weaning. Although the mortality rate of the wild-type mice of the same strain, C57BL/6, is already high, PAC1-receptor-deficient mice died twice as frequently as the wild-type and heterozygous mice before weaning. These animals were raised at a room temperature of 20–22 C, an average of 21 C (Brabet, P., personal communication). The paper by Gray et al. in this issue (6) shows that at this temperature, only 11% of the PACAP null mice survived after weaning. PACAP null mice prepared by Baba’s group (4) also showed a greater mortality within a few days after genotyping with tail cutting on d 0. The mortality rates of the wild-type, heterozygous, and homozygous animals, all of which were subjected to genotyping on d 0, were 31.7%, 25.3%, and 72.2%, respectively. Among the animals that survived after genotyping, premature death within 3–4 wk was noted only in PACAP null mice. These animals were raised at around 23 C (Baba, A., personal communication). Whether the premature death of these animals resulted from impaired adaptive thermogenesis at the relatively low temperature in the animal quarters is unknown. However, the findings suggest that PACAP null mice are also intolerant to various adverse stresses such as tail cutting for genotyping. Although the levels of catecholamines in the adrenal medulla of the PACAP null mice do not differ from the levels in the control mice, these animals showed an increased mortality after an insulin challenge due to prolonged hypoglycemia resulting from an inability to maintain sustained epinephrine release from the adrenal medulla (5). On the other hand, the administration of PACAP attenuated septic shock in mice (13) and dogs (14). PACAP also showed a significant antiinflammatory response (15).
Gray et al. (3) previously reported that PACAP null mice died in a wasted state with lipid droplets in the liver, heart, and skeletal muscles. The authors now report that the PACAP null mice raised at 24 C no longer showed the wasted state (6). However, it was not reported whether lipid deposition in the liver, heart, and skeletal muscles is still present in the PACAP null mice raised at 24 C. It is an interesting issue whether the impaired adaptive thermogenesis and abnormal lipid metabolism in the PACAP null mice are independent consequences of the absence of PACAP.
In conclusion, the report by Gray et al. in this issue (6) provides important information about the physiological role of PACAP in the adaptation of the living body to a cold environment, through adaptive thermogenesis by the brown adipose tissues. The adaptive action to the low temperature and the protective action of PACAP to other stresses appear to be mediated by its stimulatory action to sustain the production of catecholamines in the sympathetic nerves and the adrenal medulla. These findings suggest the vital role of this peptide in the protection of the living body from adverse influences and in adapting to the ever changing external environment. The vital role of PACAP in adaptation could be consistent with the highly conserved structure of PACAP during the evolution.
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Acknowledgments |
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Footnotes |
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Received August 1, 2002.
Accepted for publication August 1, 2002.
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  K. J. Cummings, C. Willie, and R. J. A. Wilson Pituitary adenylate cyclase-activating polypeptide maintains neonatal breathing but not metabolism during mild reductions in ambient temperature Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R956 - R965. [Abstract] [Full Text] [PDF]
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