Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

Abstract

We identified a glycoprotein hormone ␤-subunit (OGH, also called GPB5) that, as a heterodimer with the ␣-subunit GPA2, serves as a second ligand for the thyroid-stimulating hormone receptor. Mice in which the OGH gene is deleted (OGH ؊/؊ ) are indistinguishable from WT littermates in body weight, response to high-fat diet, metabolic parameters, body composition, and insulin tolerance. Mice engineered to transgenically globally overexpress OGH (OGH-TG) develop Ϸ2-fold elevations in their basal thyroid levels and weigh slightly less than WT littermates despite increased food intake because of an increase in their metabolic rates. Moreover, when OGH-TG mice are challenged with a high-fat diet, they gain significantly less weight and body fat than their WT littermates. The OGH-TG mice also have reduced blood glucose, insulin, cholesterol, and triglycerides. In contrast to other approaches in which the thyroid axis is activated, OGH-TG mice exhibit only minor changes in heart rate and blood pressure. Our findings suggest that constitutive low-level activation of the thyroid axis (via OGH or other means) may provide a beneficial therapeutic approach for combating diet-induced obesity.cholesterol ͉ metabolic rate ͉ thyroid T hyroid-stimulating hormone (TSH) and the TSH receptor (TSHR) are key proteins in the control of thyroid function. TSH synthesis and release is stimulated by hypothalamic TSHreleasing hormone (TRH) and is down-regulated (inhibited) by thyroid hormone in a classic endocrine negative-feedback loop. The specificity inherent in TSH resides in its unique ␤-subunit that heterodimerizes with a common ␣-subunit, which it shares with the other glycoprotein hormones [i.e., follicle-stimulating hormone (FSH), luteinizing hormone, and chorionic gonadotropin]. The primary physiological actions of TSH on the thyroid are stimulation of the synthesis and release of 3,5,3Ј,5Ј-tetraiodo-L-thyronine (T4) and 3,5,3Ј-triiodo-L-thyronine (T3) (together termed thyroid hormone) and promotion of thyroid growth; for example, it has been shown that thyroid development is arrested in mice with targeted disruption of the common ␣-subunit (1).Clinically, thyroid hormone is used primarily as a replacement therapy for the patients with hypothyroidism, and it has been considered as a possible therapy for weight reduction (because of its ability to increase metabolism and energy expenditures), for lowering cholesterol, and even to build bone (in osteoporosis). One of the major hurdles in this approach has been the cardiovascular toxicity observed after administration of the endogenous ligands T4 and T3 or nonselective thyroid hormone agonists. The two major subtypes of the thyroid hormone receptors that mediate these responses, TR␣ and TR␤, are the products of different genes and are also differentially processed to each yield two isoforms. It has been argued that modulation of heart rate and rhythm is mediated predominantly by activation of TR␣ 1 (2-4), and as a result, recent pharmaceutical research efforts have focused on develop...

The LH/CG receptor activates canonical signaling pathway when expressed in Drosophila

“…In Drosophila, a GnRH-like receptor has been identified, though its ligand belongs to the adipokinetic hormone family Staubli et al, 2002). Leucine-rich repeat (LRR) receptors structurally and evolutionary related to the mammalian gonadotropin and thyrotropin (TSH) receptors were identified in various vertebrates and invertebrates Hauser et al, 1997;Luo et al, 2005;Mendive et al, 2005;Nishi et al, 2000;Sudo et al, 2005;Van Loy et al, 2008;Sellami et al, 2011;Eriksen et al, 2000;Kudo et al, 2000;Vibede et al, 1998;McDonald et al, 1998;Nakabayashi et al, 2002;Macdonald et al, 2005). In Drosophila, these receptors (DLGRs) function in development, cuticle sceloritization and wing expansion and to maintain water homeostasis (Hauser et al, 1997;Luo et al, 2005;Mendive et al, 2005;Nishi et al, 2000;Sudo et al, 2005;Van Loy et al, 2008;Sellami et al, 2011;Eriksen et al, 2000).…”

The role of thyrostimulin and its potential clinical significance

“…Th rough observations in transgenic mice overexpressing GPB5, thyrostimulin and compounds similar but only slightly diff erent to the original molecule, thyrostimulin has been shown to possess therapeutic potential in diet-induced obesity (Macdonald et al 2005). Transgenic mice indulge in increased food intake yet weigh less than their wild type (WT) counterparts, which can be attributed to the increase in metabolic rate conferred by thyrostimulin.…”

“…Additional histological features include hypertrophy of not only thyroid cells, but also cells of the inner adrenal cortex (Okada et al 2006). Use of a thyrostimulin analogue with the classical GPB5, but a slightly altered GPA2 doubles serum T4 compared to baseline (Macdonald et al 2005). Surprisingly, knocking out GPB5 yields no overt phenotypic pathologies in mice suggesting that thyrostimulin is unlikely to be essential for the survival (Okada et al 2006;Lantz et al 2007).…”

“…Since to the best of our knowledge, no studies have reported knocking out GPA2, which might elucidate the purpose of the monomer and to show whether it is a key for binding or signaling or for the both. At this point however, it is worth mentioning that groups have knocked out GPB5 in mice and the results are discussed in detail in the following section (Macdonald et al 2005).…”

“…Juvenile GPB5KO mice show increased bone mineral content and osteoblastic bone formation rate indicative of a negative, likely catabolic role of thyrostimulin on the bone formation and mineralization (Mac- (Figure 4) (Macdonald et al 2005). Th e nasal and frontal bones in rats are derived from the neural crest, whereas the parietal bone is a mesodermal structure.…”