Circadian Neuroendocrine Role in Age-Related Changes in Body Fat Stores and Insulin Sensitivity of the Male Sprague-Dawley Rat

A role for circadian neuroendocrine rhythms in the age-related development of obesity and insulin resistance was investigated in the male Sprague-Dawley rat. The phases and amplitudes of the plasma rhythms of several metabolic hormones (i.e. corticosterone, prolactin, insulin, and triiodothyronine) differed in lean, insulin-sensitive (3-week-old rats). insulin-resistant (8-week-old rats) and obese, insulin-resistant (44-week-old rats) animals. Simulation of the daily rhythms of endogenous corticosterone and prolactin by daily injections of the hormones at times corresponding to the peak levels found in 3-week-old rats reversed age-related increases in insulin resistance and body fat in older (5-6-month-old) rats. Ten such daily injections of corticosterone and prolactin in 12-14-week-old rats produced long-term reductions in body fat stores (30%). plasma insulin concentration (40%'). and insulin resistance (60%) (determined by a glucose tolerance test) measured 11-14 weeks after the treatment. Alterations in circadian neuroendocrine rhythms may account for age-related changes in carbohydrate and lipid metabolism in the male Sprague-Dawley rat, and resetting of these rhythms by appropriately timed daily injections of corticosterone and prolactin may help maintain metabolism characteristic of younger animals.     

Genetic analysis of Pycr1 and Pycr2 in mice

The final step in proline biosynthesis is catalyzed by three pyrroline-5-carboxylate reductases, PYCR1, PYCR2, and PYCR3, which convert pyrroline-5-carboxylate (P5C) to proline. Mutations in human PYCR1 and ALDH18A1 (P5C Synthetase) cause Cutis Laxa (CL), whereas mutations in PYCR2 cause hypomyelinating leukodystrophy 10 (HLD10). Here, we investigated the genetics of Pycr1 and Pycr2 in mice. A null allele of Pycr1 did not show integument or CL-related phenotypes. We also studied a novel chemically-induced mutation in Pycr2. Mice with recessive loss-of-function mutations in Pycr2 showed phenotypes consistent with neurological and neuromuscular disorders, including weight loss, kyphosis, and hind-limb clasping. The peripheral nervous system was largely unaffected, with only mild axonal atrophy in peripheral nerves. A severe loss of subcutaneous fat in Pycr2 mutant mice is reminiscent of a CL-like phenotype, but primary features such as elastin abnormalities were not observed. Aged Pycr2 mutant mice had reduced white blood cell counts and altered lipid metabolism, suggesting a generalized metabolic disorder. PYCR1 and -2 have similar enzymatic and cellular activities, and consistent with previous studies, both were localized in the mitochondria in fibroblasts. Both PYCR1 and -2 were able to complement the loss of Pro3, the yeast enzyme that converts P5C to proline, confirming their activity as P5C reductases. In mice, Pycr1; Pycr2 double mutants were sub-viable and unhealthy compared to either single mutant, indicating the genes are largely functionally redundant. Proline levels were not reduced, and precursors were not increased in serum from Pycr2 mutant mice or in lysates from skin fibroblast cultures, but placing Pycr2 mutant mice on a proline-free diet worsened the phenotype. Thus, Pycr1 and -2 have redundant functions in proline biosynthesis, and their loss makes proline a semi-essential amino acid. These findings have implications for understanding the genetics of CL and HLD10, and for modeling these disorders in mice.     

The ubiquitin-proteasome proteolytic pathway in heart vs skeletal muscle: effects of acute diabetes

The ubiquitin-proteasome system is thought to play a major role in normal muscle protein turnover and to contribute to diabetes-induced protein wasting in skeletal muscle. However, its importance in cardiac muscle is not clear. We measured heart muscle mRNA for ubiquitin and for the C2 and C8 proteasomal subunits, the amount of free ubiquitin and the proteasome chymotrypsin-like proteolytic activity in control and diabetic rats. Results were compared to those in skeletal muscle (rectus). Heart ubiquitin, C2 and C8 subunit mRNA and proteolytic activity were significantly greater than in skeletal muscle (P 相似文献   

Extreme isotopic depletion of nitrogen in New Zealand lithophytes and epiphytes; the result of diffusive uptake of atmospheric ammonia?

Several lichens and the terrestrial alga Trentepohlia were found to have extremely depleted ¹⁵N signatures at two sites near the Rotorua geothermal area, New Zealand. Values, typically −20‰, with several extreme cases of −24‰, are more isotopically depleted than any previously quoted δ¹⁵N signature for vegetation growing in natural environments. For Trentepohlia, distance from a geothermal source did not affect isotopic signature. A 100-km transect showed that the phenomenon is widespread and the discrimination is not related to substrate N, or to elevation. Rainfall NHx and atmospheric gaseous NH₃ (NH_3(g)) were shown to be isotopically depleted in the range −1‰ to −8‰ and could not, of themselves, be responsible for the plant values obtained. A simulation of Trentepohlia thallus was created using an acidified fiberglass mat and was allowed to absorb NH_3(g) from the atmosphere. Mats exposed at the geothermal sites and on farmland showed a significant further depletion of ¹⁵N to −17‰. We hypothesize that the extreme isotopic depletion is due to dual fractionation: firstly by the volatilization of NH_3(g) from aqueous sources into the atmosphere; secondly by the diffusive assimilation of that NH_3(g) into vegetation. We further hypothesize that lithophytes, epiphytes, and higher plants, growing on strongly N-limited substrates, will show this phenomenon more or less, depending on the proportion of diffusively assimilated NH_3(g) utilized as a N source. Many of the isotopically depleted δ¹⁵N signatures in vegetation, previously reported in the literature, especially epiphytes, may be due to this form of uptake depending on the concentration of atmospheric NH_3(g), and the degree of reliance on that form of N.