BackgroundThe proper establishment of hypothalamic feeding circuits during early development has a profound influence on energy homeostasis, and perturbing this process could predispose individuals to obesity and its associated consequences later in life. The maturation of hypothalamic neuronal circuitry in rodents takes place during the initial postnatal weeks, and this coincides with a dramatic surge in the circulating level of leptin, which is known to regulate the outgrowth of key neuronal projections in the maturing hypothalamus. Coincidently, this early postnatal period also marks the rapid proliferation and expansion of astrocytes in the brain.MethodsHere we examined the effects of leptin on the proliferative capacity of astrocytes in the developing hypothalamus by treating postnatal mice with leptin. Mutant mice were also generated to conditionally remove leptin receptors from glial fibrillary acidic protein (GFAP)-expressing cells in the postnatal period.Results and conclusionsWe show that GFAP-expressing cells in the periventricular zone of the 3rd ventricle were responsive to leptin during the initial postnatal week. Leptin enhanced the proliferation of astrocytes in the postnatal hypothalamus and conditional removal of leptin receptors from GFAP-expressing cells during early postnatal period limited astrocyte proliferation. While increasing evidence demonstrates a direct role of leptin in regulating astrocytes in the adult brain, and given the essential function of astrocytes in modulating neuronal function and connectivity, our study indicates that leptin may exert its metabolic effects, in part, by promoting hypothalamic astrogenesis during early postnatal development.

Proper regulation of energy metabolism requires neurons in the central nervous system to respond dynamically to signals that reflect the body's energy reserve, and one such signal is leptin. Agouti-related protein (AgRP) is a hypothalamic neuropeptide that is markedly upregulated in leptin deficiency, a condition that is associated with severe obesity, diabetes, and hepatic steatosis. Because deleting AgRP in mice does not alter energy balance, we sought to determine whether AgRP plays an indispensable role in regulating energy and hepatic lipid metabolism in the sensitized background of leptin deficiency. We generated male mice that are deficient for both leptin and AgRP [double-knockout (DKO)]. DKO mice and ob/ob littermates had similar body weights, food intake, energy expenditure, and plasma insulin levels, although DKO mice surprisingly developed heightened hyperglycemia with advancing age. Overall hepatic lipid content was reduced in young prediabetic DKO mice, but not in the older diabetic counterparts. Intriguingly, however, both young and older DKO mice had an altered zonal distribution of hepatic lipids with reduced periportal lipid deposition. Moreover, leptin stimulated, whereas AgRP inhibited, hepatic sympathetic activity. Ablating sympathetic nerves to the liver, which primarily innervate the portal regions, produced periportal lipid accumulation in wild-type mice. Collectively, our results highlight AgRP as a regulator of hepatic sympathetic activity and metabolic zonation.

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Excessive alcohol consumption, including binge drinking, is a common cause of fatty liver disease. Binge drinking rapidly induces hepatic steatosis, an early step in the pathogenesis of chronic liver injury. Despite its prevalence, the process by which excessive alcohol consumption promotes hepatic lipid accumulation remains unclear. Alcohol exerts potent effects on the brain, including hypothalamic neurons crucial for metabolic regulation. However, whether or not the brain plays a role in alcohol-induced hepatic steatosis is unknown. In the brain, alcohol increases extracellular levels of adenosine, a potent neuromodulator, and previous work implicates adenosine signaling as being important for the development of alcoholic fatty liver disease. Acute alcohol exposure also increases both the activity of agouti-related protein (AgRP)-expressing neurons and AgRP immunoreactivity. Here, we show that adenosine receptor A2B signaling in the brain modulates the extent of alcohol-induced fatty liver in mice and that both the AgRP neuropeptide and the sympathetic nervous system are indispensable for hepatic steatosis induced by bingelike alcohol consumption. Together, these results indicate that the brain plays an integral role in alcohol-induced hepatic lipid accumulation and that central adenosine signaling, hypothalamic AgRP, and the sympathetic nervous system are crucial mediators of this process.

In an ever-changing environment where food availability is highly unpredictable, the ability to maintain energy homeostasis requires proper sensing of dietary macronutrients, and subsequent adaptive adjustments in feeding behavior. Cholesterol is an important macronutrient, but cytotoxic in excess. Thus, cholesterol metabolism is under tight homeostatic regulation. Cholesterol is a major precursor of bile acids. After a meal, bile acids are released into the intestine and stimulate the secretion of fibroblast growth factor 15/19 (FGF-15/19). FGF-15/19 is an enterokine known to specifically suppress Agouti-related protein (AgRP), a neuropeptide of the central melanocortin system (CMS) that increases with fasting and promotes feeding and locomotor activity. Studies show that the CMS plays a modulatory role in hepatic cholesterol metabolism. However, the effects of dietary cholesterol on feeding behavior and energy homeostasis have remained largely unexplored. In this study, we found, surprisingly, that dietary cholesterol modulates expression of AgRP. Specific removal of cholesterol from the diets of wild type mice under ad-lib conditions leads to increased hypothalamic Agrp, but not Npy, mRNA expression. Furthermore, these mice also have low intestinal fGF-15mRNA expression. Cholesterol deficiency also leads to increased locomotor activities, an effect that is AgRP dependent as locomotor activity in AgRP knockout mice is unaffected by alterations in dietary cholesterol content. In wild type mice, fasting induces increased locomotor activity, which is widely thought to be a proxy for food seeking behavior. Notably, we observe dietary cholesterol content has no effect on ad-libfood intake, suggesting food seeking behaviors may be uncoupled from food intake. Taken together, these results suggest a novel paradigm where dietary cholesterol can act as a peripheral nutrient signal that can ultimately affect locomotor activity and possibly food seeking behavior. Disclosure A. Huang: None. M.T. Maier: None. A. Xu: None.