Editors' ChoiceDiabetes

Diabetes: The roles of brains, brawn, and brown fat?

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Science Translational Medicine  27 Apr 2016:
Vol. 8, Issue 336, pp. 336ec66
DOI: 10.1126/scitranslmed.aaf7824

The global prevalence of obesity has increased dramatically, with a consequent increase in complications such as diabetes. Maintenance of normal weight relies on CNS circuits that integrate hormonal, nutrient, and sensory cues to balance energy intake and expenditure. A hypothalamic neural population expressing the peptide Agouti-related peptide (AgRP) is thought to be key to several of these circuits. Now, Steculorum et al. have shown that AgRP neurons also acutely control glucose metabolism by altering brown fat (BAT).

The authors used light and chemical tools to acutely switch on AgRP neurons. When they did so, mice not only ate more but quickly became glucose intolerant and insulin resistant, primarily through reduced insulin-stimulated glucose uptake into BAT. The group found that switching on AgRP neurons reduced sympathetic activation of BAT and dramatically altered its gene profile, increasing the expression of muscle-associated genes. Among the most highly up-regulated genes was myostatin, a gene that is also up-regulated in obesity. When brown adipocytes were pretreated with myostatin, the effects of insulin were blunted. Conversely, treating mice with a myostatin-blocking antibody reduced the insulin resistance produced by activating AgRP neurons. In a final set of studies, the researchers investigated which AgRP circuits were capable of altering myostatin expression and glucose metabolism and whether these circuits were separate from those regulating appetite. AgRP neurons projecting to several areas were capable of increasing appetite, but only AgRP neurons projecting to a specific subdivision of the bed nucleus of the stria terminalis—an area important in processing reward signals—increased myostatin expression and reduced insulin sensitivity without altering feeding.

This study links AgRP neural activity with impaired glucose tolerance through altered BAT function and myostatin expression. If a similar circuit is present in humans, the activity of this circuit and myostatin in glucose metabolism may be a potential avenue for therapeutic strategies.

S. M. Steculorum et al., AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165, 125–138 (2016). [Abstract]

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