Rapid oscillations of visceral lipolysis have been reported. To examine the putative role of the CNS in oscillatory lipolysis, we tested the effects of β3-blockade on pulsatile release of FFAs. Arterial blood samples were drawn at 1-minute intervals for 120 minutes from fasted, conscious dogs (n = 7) during the infusion of saline or bupranolol (1.5 μg/kg/min), a high-affinity β3-blocker. FFA and glycerol time series were analyzed and deconvolution analysis was applied to estimate the rate of FFA release. During saline infusion FFAs and glycerol oscillated in phase at about eight pulses/hour. Deconvolution analysis showed bursts of lipolysis (nine pulses/hour) with time-dependent variation in burst frequency. Bupranolol completely removed rapid FFA and glycerol oscillations. Despite removal of lipolytic bursts, plasma FFAs (0.31 mM) and glycerol (0.06 mM) were not totally suppressed and deconvolution analysis revealed persistent non-oscillatory lipolysis (0.064 mM/min). These results show that lipolysis in the fasting state consists of an oscillatory component, which appears to be entirely dependent upon sympathetic innervation of the adipose tissue, and a non-oscillatory, constitutive component, which persists despite β3-blockade. The extinction of lipid fuel bursts by β3-blockade implies a role for the CNS in the maintenance of cyclic provision of lipid fuels.
Katrin Hücking, Marianthe Hamilton-Wessler, Martin Ellmerer, Richard N. Bergman
Shouhong Xuan, Tadahiro Kitamura, Jun Nakae, Katerina Politi, Yoshiaki Kido, Peter E. Fisher, Manrico Morroni, Saverio Cinti, Morris F. White, Pedro L. Herrera, Domenico Accili, Argiris Efstratiadis
Shoshana Yakar, Clifford J. Rosen, Wesley G. Beamer, Cheryl L. Ackert-Bicknell, Yiping Wu, Jun-Li Liu, Guck T. Ooi, Jennifer Setser, Jan Frystyk, Yves R. Boisclair, Derek LeRoith
Timothy G. Butler, Jeff Schwartz, I. Caroline McMillen
Kathrin Maedler, Pavel Sergeev, Frédéric Ris, José Oberholzer, Helen I. Joller-Jemelka, Giatgen A. Spinas, Nurit Kaiser, Philippe A. Halban, Marc Y. Donath
Lara B. Pupim, Paul J. Flakoll, John R. Brouillette, Deanna K. Levenhagen, Raymond M. Hakim, T. Alp Ikizler
Norma Fox, Greg Priestley, Thalia Papayannopoulou, Kenneth Kaushansky
Obesity is the result of an imbalance between energy intake and energy expenditure. Using high-density DNA microarrays and Northern analyses, we demonstrated that the activation of a nutrient-sensing pathway, the hexosamine biosynthesis pathway (HBP), rapidly decreased the expression of a cluster of nuclear-encoded mitochondrial genes involved in skeletal muscle oxidative phosphorylation. Conversely, the expression of uncoupling protein-1 and of the same mitochondrial genes was increased in brown adipose tissue. Most important, these transcriptional changes were accompanied by a marked decrease in whole-body energy expenditure. Short-term overfeeding replicated this transcriptional pattern, suggesting that this adaptation to nutrient abundance occurs under physiological conditions. Thus, the activation of the HBP by nutrients represents a biochemical link between nutrient availability, mitochondrial proteins, and energy expenditure, and it is likely to play an important role in the regulation of energy balance.
Silvana Obici, Jiali Wang, Rahena Chowdury, Zhaohui Feng, Uma Siddhanta, Kimyata Morgan, Luciano Rossetti
Growth hormone secretagogues (GHSs) stimulate GH secretion and food intake. GHS receptor (GHS-R) mRNA has been identified mainly in the arcuate nucleus (Arc) and ventromedial nucleus of the hypothalamus and in the pituitary. Ghrelin, an endogenous ligand for GHS-R, has recently been purified from rat stomach. Although ghrelin is also expressed in the hypothalamus, the physiological significance of the ghrelin/GHS-R system is still unknown. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase (TH), thus selectively attenuating GHS-R protein expression in the Arc. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma insulin-like growth factor-I levels were reduced in female Tg rats. These results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity.
Yujin Shuto, Tamotsu Shibasaki, Asuka Otagiri, Hideki Kuriyama, Hisayuki Ohata, Hideki Tamura, Jun Kamegai, Hitoshi Sugihara, Shinichi Oikawa, Ichiji Wakabayashi
Human thyrotropin (TSH), luteotropin (LH), follitropin (FSH), and chorionic gonadotropin are members of the heterodimeric glycoprotein hormone family. The common α subunit forms noncovalent heterodimers with different β subunits. Two novel human glycoprotein hormonelike genes, α2 (A2) and β5 (B5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners. Immunological analyses confirmed the heterodimerization of A2 and B5 in transfected cells and their colocalization in the anterior pituitary. Recombinant A2/B5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human TSH receptors, but not LH and FSH receptors, and showed high affinity to TSH receptors in a radioligand receptor assay. The heterodimer also stimulated cAMP production and thymidine incorporation by cultured thyroid cells and increased serum thyroxine levels in TSH-suppressed rats in vivo. This new heterodimeric glycoprotein hormone was named as thyrostimulin based on its thyroid-stimulating activity. The expression of thyrostimulin in the anterior pituitary known to express TSH receptors suggested a paracrine mechanism. The present discovery of a new ligand based on genomic approaches could facilitate the understanding of the physiological roles of extra-thyroid TSH receptor systems and the structural-functional basis of receptor signaling by related glycoprotein hormones.
Koji Nakabayashi, Hirotaka Matsumi, Alka Bhalla, Jeehyeon Bae, Sietse Mosselman, Sheau Yu Hsu, Aaron J.W. Hsueh