Although research on leptin action has emphasized the role of hypothalamic mediators, leptin receptors are expressed throughout the brain, and extrahypothalamic receptor populations can clearly mediate leptin effects. Activation of leptin receptors in the hindbrain reduces food intake while increasing energy expenditure such that body weight is reduced (9
). Moreover, the mechanism whereby leptin action in both hypothalamus and hindbrain reduces overall food intake involves an enhanced response to the satiating effect of short-term signals such as CCK (10
In the hypothalamus, leptin action depends critically (though not exclusively) on two arcuate nucleus (ARC) neuronal types: those expressing proopiomelanocortin (POMC), the precursor for the anorexigenic neuropeptide α-melanocyte-stimulating hormone, and those coexpressing agouti-related protein (AgRP) and neuropeptide Y (NPY), both orexigenic neuropeptides (1
) (Figure ). Far less is known about neuronal populations that mediate leptin’s effects in the hindbrain. POMC is expressed in the NTS, but the sensitivity of hindbrain POMC neurons to leptin is controversial (14
). AgRP is not expressed in hindbrain, and leptin receptors are not expressed by hindbrain NPY neurons (16
). In mouse (but not in rat) hindbrain, leptin receptors are expressed in glucagon-like 1 peptide (GLP-1) neurons, and leptin regulates expression of mRNA for proglucagon, the peptide precursor of GLP-1 (17
). Thus, despite similarities in feeding effects of forebrain and hindbrain leptin treatment, the neural circuitry engaged by leptin differs across these regions.
Hypothalamic and hindbrain neurocircuits that regulate food intake and energy expenditure in response to input from the adipocyte hormone leptin.
High-fat diet (HFD) feeding offers another example of a difference between leptin action in hypothalamus versus the hindbrain. During HFD feeding, body fat mass and circulating leptin levels increase, and reduced sensitivity to exogenous leptin — leptin resistance — can develop rapidly. To the extent that leptin resistance contributes to obesity pathogenesis in this setting, as many have suggested (19
), the deficit appears localized to the hypothalamus, because HFD-induced impairment of leptin signaling occurs in the ARC but not the NTS (20
Scott and colleagues’ (2
) deletion of leptin receptors from Phox2b-expressing neurons is the first report of cell type–specific manipulation of leptin signaling in mouse hindbrain. Although the neurochemical identity of the hindbrain cells targeted remains to be fully ascertained, GLP-1 neurons are among those in which leptin receptor deletion occurred. The finding that Phox2b Cre Leprflox/flox
(PC flox) mice display both increased food intake and an exaggerated hyperphagic response to an overnight fast suggests that in normal mice, leptin signaling in GLP-1 and/or other hindbrain neurons constrains these behaviors. Yet the body fat content of PC flox mice was not increased, evidently because their metabolic rate increased so as to maintain neutral energy balance. Thus, although leptin action in Phox2b-expressing hindbrain neurons appears to play a physiological role to limit food intake, loss of leptin signaling in these cells does not prevent the detection of and compensation for this perturbation of energy balance.
The conclusion that increased energy expenditure in PC flox mice results from, rather than causes, hyperphagia derives from the finding that their hypermetabolic phenotype was eliminated during a fast and hence depends upon food consumption. Interestingly, the ability of leptin to reduce food intake and body weight was not attenuated in these mice, suggesting that leptin signaling in the subset of hindbrain neurons that express the Phox2b promoter is not required for leptin’s anorexic effect. Moreover, the differences of food intake and energy expenditure between controls and PC flox mice disappeared when they were placed on a HFD.
This constellation of features is unique, and it differs in important ways from the phenotypes of mice in which leptin receptors are deleted from hypothalamic neurons. Mice lacking leptin receptors in POMC neurons eat the same amount of food as controls but have increased body weight as a result of reduced energy expenditure (5
). Leptin receptor deletion in neurons of the ventromedial hypothalamic nucleus produces a similar phenotype, although energy intake increases when the mice are placed on a HFD (4
). Deletion of leptin receptors in NPY/AgRP neurons also increases body weight via yet another a mechanism involving reductions of locomotor activity and body temperature, and a somewhat greater obesity results when leptin receptors are deleted from both NPY/AgRP and POMC cells, due to combined effects of hyperphagia and reduced energy expenditure (3
). Therefore, loss of hypothalamic leptin signaling consistently favors positive energy balance and obesity, whereas PC flox mice maintain near-normal energy balance because increases of energy intake and expenditure offset one another.
It is worth noting that less selective leptin receptor deletion strategies invariably have more robust effects. For example, targeted deletion of leptin receptors from all hypothalamic neurons causes pronounced hyperphagia and obesity (21
), and Hayes and colleagues (10
) recently showed that shRNAi-induced knockdown of leptin receptor expression in the NTS and AP increases food intake and body weight, although the effect is modest by comparison. The differences between the phenotypes of these and aforementioned, more selective models highlights the complexity of the circuitry that mediates leptin’s effects and emphasizes both the importance of and the limitations inherent in cell type–specific strategies for delineating the roles of distinct neuronal populations.