To B or not to B: Fat is the question

In the early 1970s, the screening of over 500 amphibian species led to the discovery by two independent investigators of several structurally related peptides from amphibian skin now referred to as the bombesin (BN) family of peptides. These peptides were classified into three subfamilies (bombesin, ranatensin and litorin) based on their carboxy terminal amino acid sequences. Subsequently, two mammalian peptides were identified that showed remarkable sequence homology with other members of this family. Neuromedin B (NMB), a decapeptide originally isolated from porcine spinal cord, bears close structural homology with ranatensin whereas gastrin-releasing peptide (GRP) isolated from porcine stomach shares the same carboxy terminal heptapeptide sequence with BN and similar biological activity. In mammals, this family of peptides is composed of three known subtypes of closely related G-protein-coupled receptors. Two subtypes, neuromedin B receptor (NMB-R or BB1) and gastrin-releasing peptide receptor (GRP-R or BB2), were initially identified and characterized in the periphery and brain by pharmacological methods. GRP-R was shown to have a greater than 50-fold higher affinity for GRP than NMB, while NMB-R had a 100-fold higher affinity for NMB than GRP. Subsequently, these receptors were cloned, and an additional mammalian BN receptor subtype, BN receptor subtype-3 (BRS-3 or BB3) was identified through homology screening and found to share approximately 50% identity with GRP-R and NMB-R; however, the natural ligand for this receptor has not been identified. These peptides have distinct distributions throughout the periphery and central nervous system and possess a wide spectrum of biological activity. Many of the actions of NMB are similar to those of BN or GRP but are frequently less potent in stimulating these actions. In the periphery, NMB has been shown to contract rat uterus and gastrointestinal smooth muscle and stimulate the release of several gastrointestinal and pancreatic peptides. Relevant to this discussion, exogenous administration of BN-like peptides suppresses food intake after either peripheral or central administration with the rank order of inhibition being BN > GRP > NMB. The development of specific BN receptor antagonists was instrumental in demonstrating that NMB acted independently of GRP to suppress food intake. However, the lack of a robust effect on food intake made it the ‘underdog’ of bombesin-like peptides and consequently it received very limited attention as a satiety peptide. Because of complications in interpreting much of the pharmacological data, Ohki-Hamazaki and colleagues developed mice with specific deletions of the three mammalian BN receptor subtypes to help elucidate their physiological roles (Ohki-Hamazaki et al. 2005). It was found that deletions of BRS-3 resulted in an obese phenotype with deficits in energy regulation and an increased preference for sweet taste. Mice lacking GRP-R exhibited deficits in meal-related satiety signalling and developed late onset obesity. Despite an apparent role for NMB in food intake, the phenotype of mice with a targeted deletion of NMB-R could only be characterized as unremarkable. Mice deficient in NMB-R exhibited normal body weight and chow intake, and showed no differences in taste preference for palatable foods compared to wild-type mice. However, a variety of behavioural tests in NMB-R knockout (KO) mice have suggested that NMB plays a role in anxiety and stress-related behaviours. In this issue of The Journal of Physiology, Paula et al. (2010) have conducted experiments in female NMB-R-deficient mice that reveal a previously undetected phenotype with important implications in food intake and energy balance. As reported previously, when female NMB-R KO mice were fed a standard chow diet their food intake and body weight did not differ from wild-type (WT) mice. However, when challenged with a high-fat diet NMB-R KO mice were partially resistant to the obesogenic effects of the high fat diet. Remarkably, NMB-R KO mice consumed the same number of calories as WT mice but failed to gain significant body weight. Consistent with this, the authors demonstrate that high-fat-fed NMB-R KO mice exhibited less adipose tissue hypertrophy and adipose tissue mass than similarly fed WT mice. Because no differences in adipose tissue mass were demonstrated between NMB-R KO and WT mice fed a normolipid diet, the authors suggest that NMB-R KO mice must increase their energy expenditure in response to high-fat feeding. Unlike high-fat-fed WT mice, NMB-R KO mice did not exhibit impairments in glucose tolerance. Since NMB-KO mice were consuming the same amount of food as WT mice, this suggests that diet composition alone was not contributing to impaired glucose tolerance but that the latter was probably dependent upon increased body weight. The results of this study highlight a renewed interest in NMB as an important component in energy balance regulation. Recent studies have shown NMB and NMB-R to be significant regulators of the hypothalamic-pituitary-adrenal axis through modulation of thyrotropin secretion (Oliveira et al. 2007). Studies by Hoggard et al. (2007) have demonstrated that NMB mRNA is present in human and rodent adipose tissue and that expression levels can be altered by changes in energy balance and leptin signalling. Moreover, electrophysiological studies have shown a robust excitatory effect of NMB on neuropeptide Y neurons in the arcuate nucleus, a brain region that is critical to energy homeostasis (von den Pol et al. 2009). In humans, NMB has been suggested as a strong candidate gene linking eating behaviours to the susceptibility to obesity (Bouchard et al. 2004). The Quebec Family Study, a large prospective study designed to identify the genetics of obesity and related diseases, found that a missense mutation within exon 2 of the NMB gene was significantly associated with eating behaviours and obesity. This mutation resulted in twice as much body fat gain over a 6 year period compared to those without the mutation. How these data mesh with the results from the present study remains to be determined; however, they do suggest that NMB/NMB-R pathways may play a critical role in adipose tissue deposition or metabolism and provide a potential target for therapeutic intervention in the control of body weight.

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