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Division of Endocrinology/Metabolism, VA Puget Sound Health Care System; and Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98108
Address all correspondence and requests for reprints to: Denis G. Baskin, Division of Endocrinology/Metabolism, VA Puget Sound Health Care System; and Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98108. E-mail: baskindg{at}u.washington.edu.
Hypothalamic neurons that secrete melanocortins are viewed as playing a central role in the regulation of energy homeostasis because they act at brain melanocortin receptors to mediate the anorectic effects of leptin (1). It has been well established that food intake and energy expenditure are regulated in part by two opposing ligands of central melanocortin receptors, 
-MSH and agouti-related protein (AgRP) (also known as agouti-related peptide), which have opposing actions at central nervous system (CNS) melanocortin receptors (2). Because disruptions of the CNS melanocortin system are associated with disorders of food intake in animal models and humans (3), information about the neuroanatomic and molecular underpinnings of this system is critical to understanding the normal regulation of body weight as well as disorders of body weight and obesity.
Leptin inhibits synthesis of neuropeptide Y (NPY) and AgRP, which are coexpressed in NPY/AgRP neurons of the arcuate nucleus. Both are powerful agents for stimulating food intake. Simultaneously, leptin stimulates the expression of the pomc gene in a separate population of arcuate nucleus cells that synthesize proopiomelanocortin (POMC), the precursor protein of a variety of bioactive peptides including -MSH. -MSH acts as an agonist at both melanocortin-3 receptors and melanocortin-4 receptors (Mc4r) to produce anorectic effects: decreased food intake and increased energy expenditure. In contrast, AgRP acts as an antagonist of the Mc4r, effectively competing with -MSH at downstream neurons that receive axonal inputs from both NPY/AgRP neurons and POMC neurons that function in energy homeostasis. Loss-of-function mutations in mc4r result in obesity in mice (4, 5) and humans (6, 7).
These NPY/AgRP and POMC cells are thought to be first-order primary neurons in the CNS that respond to adiposity signals such as leptin, which provides a long-term anorectic signal to the brain about the size of adipose tissue mass (1). AgRP and -MSH are released elsewhere in the brain to act on second-order neurons that express Mc4r receptors. These latter neurons interact with unidentified downstream neurons in circuits that ultimately determine ingestive behavior and autonomic nervous system activity. These second-order neurons with Mc4r were thought to reside primarily in the hypothalamic paraventricular nucleus (PVN) and to a lesser extent the lateral hypothalamic area (LHA).
Although it was not known for certain, the field had generally assumed—mainly for lack of evidence to the contrary—that a common population of melanocortin-responsive neurons regulate both food intake and energy expenditure. Nevertheless, a hint of a possible anatomical dissociation between the food intake and energy expenditure regulating pathways of CNS melanocortin signaling was indicated by findings that mc4r knockout mice are hyperphagic but do not regulate pathways that increase energy expenditure (5, 8). This view of a unified melanocortin signaling system has been challenged by several recent papers that indicate that food intake and energy expenditure are regulated by anatomically distinct populations of neurons that secrete melanocortin peptides and express melanocortin receptors (9).
A recent paper by Balthasar et al. (10) demonstrated that restoration of mc4r gene expression in the PVN attenuated the hyperphagia of mc4r knockout mice, whereas energy expenditure was unaffected. These findings raised fundamental questions of what is different about the melanocortin signaling pathways that regulate food intake and energy expenditure, as food intake and energy homeostasis appear to be regulated by separate populations of melanocortin-sensitive neurons. Are the downstream target neurons that express melanocortin receptors different for food intake and energy expenditure regulation circuits? What are the molecular mechanisms that permit certain neurons that express Mc4r receptors to modulate food intake in response to melanocortin ligands while others do not?
The article by Kublaoui et al. (11) in this issue of Endocrinology sheds new light on these questions. In a series of studies, this group of investigators from the laboratory of Andrew Zinn at the University of Texas Southwestern Medical Center at Dallas has been resolute in pursuing the role of the Sim1 gene in energy homeostasis. The name Sim1 derives from the single-minded gene family in Drosophila. The Sim1 gene was identified in Drosophila, where it plays a critical role in the development of the midline neuroepithelium during embryonic development (12, 13), and evidence suggests that it is also important for the correct targeting of axons in the mammalian CNS (14). It belongs to a group of nuclear transcription factors called the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of nuclear transcription factors, which include Sim1 and Sim2 (15). Haploinsufficiency and disruption of SIM1, the homolog of Sim1 in humans, are associated with hyperphagic obesity (12, 16, 17) and Down syndrome (12). Sim1 is also expressed in mice (18), where Sim1 heterozygotes (Sim1+/–) have a phenotype similar to that of the agouti yellow Ay and mc4r knockout mice; all exhibit hyperphagia, obesity, increased linear growth, and susceptibility to diet-induced obesity (19). The Sim1+/– heterozygotes, however, do not show decreased energy expenditure (20). Further linking Sim1 to melanocortin functions are the findings that Sim1 is expressed mainly in the PVN, LHA, and amygdala, regions that also have high concentrations of mc4r-expressing neurons (10, 21, 22). Moreover, Mc4r receptors are specifically expressed in Sim1 neurons of the PVN and the amygdala (10). Sim1+/– heterozygotes exhibit abnormal neuroendocrine development of the PVN (8, 20) and are resistant to the anorectic effects of melanocortin signaling, although the numbers of Sim1-positive neurons appear to be normal (23).
In a related paper, Kublaoui et al. (23) have shown that all PVN neurons of the adult mouse express Sim1 and that the regulation of food intake by signaling via Mc4r in the PVN is dependent on Sim1. Furthermore, the melanocortin agonist, MTII, induced c-Fos expression in a subset of the PVN Sim1 neurons in wild-type mice but not in Sim1+/– heterozygotes, a finding that suggests that Sim1 is a critical component of the hypothalamic melanocortin signaling for regulation of food intake and that it probably acts downstream of the Mc4r receptor (23).
In the present paper, Kublaoui et al. (11) add more evidence to the model of Sim1 regulation of melanocortin regulation of food intake independent of energy expenditure. They hypothesize that an interaction between Sim1 and mc4r in appetite regulation may be due to abnormal transcriptional regulation of target genes impinging on the downstream pathways of Mc4r signaling. To test this hypothesis of Sim1 regulation of Mc4r signaling in adult mice, they overexpressed human SIM1 via a BAC transgene and tested the effect of this overexpression on body weight and energy expenditure by feeding weaned animals a high-fat vs. low-fat diet for 3 wk. The strategy assumed that the enhancement of anorectic melanocortin signaling that would result from weight gain on a high-fat diet (presumably due to increased leptin signaling to the CNS) would be attenuated in the presence of the increased SIM1 expression in neurons bearing the Mc4R receptor. The results bore out this prediction, as mice with the SIM1 transgene showed no weight gain compared with wild-type littermates on a low-fat diet, but on a high-fat diet the SIM1 transgenic mice gained less weight and showed lowered food intake than did the wild-type mice. In energy expenditure, body composition, and activity measurements, as well as metabolic measurements, SIM1 mice were normal on both high- and low-fat diets, but the SIM1 transgenic mice had significantly less body fat compared with wild-type littermates. In response to the high-fat diet, the SIM1-overexpressing mice also did not show the normal hypothalamic response to a high-fat diet; neither NPY/AgRP nor POMC gene expression was changed. Finally, they showed that expression of the SIM1 transgene in agouti yellow Ay mice partially rescued the obesity and normalized food intake without an effect on feeding efficiency. Therefore, these results, coupled with those of their recent paper published in Molecular Endocrinology (23), make a strong case for the view that neurons that coexpress mc4r and Sim1 in the PVN (and possibly the amygdala) function solely in the control of food intake, whereas energy expenditure is regulated by mc4r-expressing neurons elsewhere in the brain.
These findings raise provocative and unanswered questions about CNS melanocortin regulation of energy homeostasis. First, what is the molecular mechanism that links the interaction between the gene products of Sim1 and mc4r and the regulation of food intake? Sim1 does not appear to regulate mc4r because mc4r expression is not reduced in Sim1 heterozygotes (11, 23). The transcriptional products of Sim1 and its heterodimers are not well understood. We need to find out what these products are and how they regulate signaling downstream of the Mc4r receptor. Moreover, we need information as to whether these gene products or the molecules involved in Sim1 function are metabolically or nutritionally regulated. Leptin and MTII induce hypothalamic Sim1 expression, but we have little or no information about the mechanisms involved. This is an important area for future research, as elucidation of the mechanism of Sim1 regulation may offer clues to new targets for drug-based therapy for obesity and other disorders of energy balance.
Second, what are the phenotypes and connections of PVN and other downstream neurons that coexpress Sim1 and mc4r and regulate the anorexic effects of melanocortins on food intake? It is becoming clear that the anorexic effects of leptin involve pathways that converge on the caudal brain stem, particularly a region known as the nucleus tractus solitarius (NTS). The NTS receives meal-related signals from the intestines via the vagus (and other routes). These include satiety signals resulting from the release of hormones such as cholecystokinin from the gut (24). The pathways that connect melanocortin expression in the arcuate nucleus to downstream neurons elsewhere in the brain appear to include the PVN and the LHA, although the identity of the cells in these regions expressing mc4r, potential candidates for mc4r regulation of food intake by Sim1, is not well described. PVN neurons that synthesize TSH releasing hormone express mc4r (25) and are activated by -MSH (26). It is tempting to speculate that PVN oxytocin neurons may also express mc4r because parvocellular PVN neurons that project to the NTS are activated by leptin, and the oxytocin innervation of the NTS appears to modulate the synergistic interaction of leptin and cholecystokinin on reduction of meal size (27, 28). To make the situation more complex, melanocortin signaling in the brainstem also modulates food intake (29, 30, 31) and may play a role in thermogenesis (32). Interestingly, Sim1 expression has not been found in the mouse NTS and related areas involved in food intake (10). These questions offer fertile ground for future studies to unravel the complex mechanisms that link melanocortin signaling to the regulation of food intake and energy expenditure by the CNS.
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Abbreviations: AgRP, Agouti-related protein; CNS, central nervous system; LHA, lateral hypothalamic area; Mc4r, melanocortin 4 receptor; NPY, neuropeptide Y; NTS, nucleus tractus solitarius; POMC, proopiomelanocortin; PVN, paraventricular nucleus.
Received June 15, 2006.
Accepted for publication June 20, 2006.
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