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Is diabetes a disease of the central nervous system? New data point in that direction. Alterations of the levels of long chain fatty acids in the hypothalamus are now shown to influence glucose homeostasis (pages 756­761).
>From the bench to the clinic, the past decade has been an exhilarating ride for diabetes and obesity researchers. Molecular mechanisms of insulin action have been identified and, since the discovery of leptin1, several brain circuits that control body weight have come to light. The pace of discovery shows no hint of slowing down. New findings continue to merge previously distinct neurobiological models of obesity and metabolic models in the liver, adipocytes and skeletal muscle.


In this issue2, Obici et al. continue this trend, adding long-chain fatty acids (LCFAs) to the growing list of metabolic signals with physiologically relevant actions in the hypothalamus. Their analysis suggests that in addition to regulating food intake and body weight, hypothalamic circuits also regulate insulin action, providing insight into potential links between type 2 diabetes and obesity.


Their findings also add fuel to arguments that some of the molecular defects underlying type 2 diabetes reside in the central nervous system (CNS)3. Taken to an admittedly audacious extreme, the study supports the concept that type 2 diabetes is a hypothalamic disorder.

 



 

 
        
Neurons rely mainly on glucose for their energy needs, but they apparently retain the ability to respond to changing levels of fatty acids. Previous studies showed that inhibitors of the enzyme fatty acid synthase (FAS) reduce food intake by inducing a buildup of the three-carbon intermediate of fatty acid biosynthesis, malonyl-CoA4. Malonyl-CoA inhibits the enzyme carnitine palmitoyltransferase-1, which is required for entry of LCFAs into mitochondria, where they are oxidized.

Obici et al. extend these findings and propose that the mechanism of action of FAS inhibitors does not simply involve increasing concentrations of malonyl-CoA that subsequently inhibit the flux of LCFAs into the mitochondria. Instead, the critical component may be an intracellular increase in LCFAs themselves that then induces a still ill-defined sensing mechanism in hypothalamic neurons. This is in agreement with their previous observations that hypothalamic infusions of fatty acids decrease food intake and glucose production5.

The authors go on to show that increases in LFCAs not only decrease food intake, but also reduce glucose production by the liver. These results and other recent findings suggest that manipulation or dysregulation of hypothalamic pathways can induce hallmarks of type 2 diabetes: hyperinsulinemia, decreased glucose uptake and increased hepatic glucose production.

The results also jibe with those of Wortman et al.6, who recently showed that accumulation of hypothalamic malonyl-CoA is not sufficient to reduce food intake. Instead, they found that FAS inhibitors decreased food intake only in the presence of physiological concentrations of blood glucose. The findings of Wortman et al. suggest that there is a complex interplay between CNS glucose and LCFAs that contributes to coordinated regulation of body weight homeostasis. Perhaps even interactions between components of modern diets (such as high fat and high carbohydrates) might directly influence hypothalamic signaling.

How might LCFAs regulate cellular events? That remains to be determined, but recent studies have indicated that fatty acids act as membrane ligands of G-protein-coupled receptors7, 8. Whatever the molecular mechanism, LCFAs may now be viewed as CNS signaling molecules, and FAS and carnitine palmitoyltransferase-1 as potential pharmaceutical targets for the treatment of obesity and diabetes.

 



 

 
        
The findings of Obici et al. also strengthen the viewpoint that some type 2 diabetes defects are due to altered responsiveness of key hypothalamic neurons to metabolic cues, including leptin, ghrelin, insulin, glucose and fatty acids. If this view is correct, then what are the central pathways underlying these responses?

In recent years, hypothalamic neurons in the arcuate nucleus have moved to the front of the investigative queue in studies investigating mechanisms of body weight homeostasis (Fig. 1). Key players in the arcuate nucleus are pro-opiomelanocortin (the precursor for the melanocortin receptor agonist, -melanocyte-stimulating hormone) and agouti-related peptide (an endogenous melanocortin receptor antagonist) neurons. The metabolic hormones leptin and ghrelin, for example, act on these neuronal populations9, 10. The changes in fatty acids reported by Obici et al. seem to be occurring in the vicinity of the arcuate nucleus. If arcuate neurons are the first responders to altered levels of key hormones and metabolites, then downstream neuronal targets are likely to include neurons expressing melanocortin-4 receptors (MC-4Rs).

The central melanocortin system is well known for its role in regulating food intake and body weight11, 12. Less appreciated is its role in regulating insulin release and insulin action3, 13. Melanocortin signaling acutely affects insulin levels and glucose uptake, for example, and humans with MC-4R mutations are extremely insulin resistant (more so than would be predicted by their degree of obesity)12-14. The MC-4R-expressing sites mediating these glucose homeostatic responses remain to be identified. However, sympathetic and parasympathetic preganglionic neurons both express MC-4Rs15, suggesting that melanocortins can directly regulate autonomic responses, including insulin secretion and insulin sensitivity in tissues such as fat and skeletal muscle. Notably, the melanocortin system may be just one of many central circuits that mediate responses to fatty acid inhibitors, as these compounds can act in the absence of melanocortin receptor signaling16.

Despite alarming increases in the incidence of obesity and diabetes, exactly why one can lead to the other is not clear. Moreover, effective drugs to treat both conditions remain to be identified. But it is possible that compounds that decrease food intake may also increase insulin sensitivity in the liver, muscle, and adipose tissue. However, direct experimental evidence linking the onset of type 2 diabetes and hypothalamic resistance to insulin, leptin and changes in glucose and fatty acids is noticeably lacking. This certainly represents a major hole in this fast-moving field.