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
Adiponectin, an adipocyte-derived hormone, was recently shown to have potential therapeutic applications in diabetes and obesity because of its influence on glucose and lipid metabolism. We found that brown fat in normal human bone marrow contains this protein and used marrow-derived preadipocyte lines and long-term cultures to explore potential roles in hematopoiesis. Recombinant adiponectin blocked fat cell formation in long-term bone marrow cultures and inhibited the differentiation of cloned stromal preadipocytes. Adiponectin also caused elevated expression of cyclooxygenase-2 (COX-2) by these stromal cells and induced release of prostaglandin E2 (PGE2). The COX-2 inhibitor Dup-697 prevented the inhibitory action of adiponectin on preadipocyte differentiation, suggesting involvement of stromal cell–derived prostanoids. Furthermore, adiponectin failed to block fat cell generation when bone marrow cells were derived from B6,129SPtgs2tm1Jed (COX-2+/–) mice. These observations show that preadipocytes represent direct targets for adiponectin action, establishing a paracrine negative feedback loop for fat regulation. They also link adiponectin to the COX-2–dependent PGs that are critical in this process.
Takafumi Yokota, C.S. Reddy Meka, Kay L. Medina, Hideya Igarashi, Phillip C. Comp, Masahiko Takahashi, Makoto Nishida, Kenji Oritani, Jun-ichiro Miyagawa, Tohru Funahashi, Yoshiaki Tomiyama, Yuji Matsuzawa, Paul W. Kincade
Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKβ, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKβ activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (∼7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a ∼25% reduction in fasting plasma glucose, associated with a ∼15% reduction in total cholesterol and C-reactive protein, a ∼50% reduction in triglycerides, and a ∼30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by ∼20% and ∼50%, respectively. Aspirin treatment also resulted in a ∼20% reduction in basal rates of hepatic glucose production and a ∼20% improvement in insulin-stimulated peripheral glucose uptake under matched plasma insulin concentrations during the clamp. In conclusion, these data support the hypothesis that IKKβ represents a new target for treating type 2 diabetes mellitus.
Ripudaman S. Hundal, Kitt F. Petersen, Adam B. Mayerson, Pritpal S. Randhawa, Silvio Inzucchi, Steven E. Shoelson, Gerald I. Shulman
Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.
Kitt Falk Petersen, Elif Arioglu Oral, Sylvie Dufour, Douglas Befroy, Charlotte Ariyan, Chunli Yu, Gary W. Cline, Alex M. DePaoli, Simeon I. Taylor, Phillip Gorden, Gerald I. Shulman