MICROGLIA: Maintenance of Hypothalamic Function Immune cells perform a previously unsuspected role in the brain that may contribute to obesity, according to a new study by UC San Francisco researchers. As opposed to classically defined inflammation, in which immune cells build up in tissues where environmental insults have created disarray, microglial activation in the brain may be a part of a normal physiological process to remodel brain function in response to changes in the composition of food intake, Koliwad said. Microglia, as subspecies of Macrophage, act in far more important and interesting ways, just as do all Macrophage cells, not just to react in narrow stereotyped immune fashion to extrernal inflammatory events, ....but both these cells show that immunity is more properly viewed as a totally encompassing maintenance and regulatory function...including food and saturated fat intake as only one of the countless ways in which immune function needs to redefined more broadly. According to the senior scientist for the study, Suneil Koliwad, MD, PhD, an assistant professor of medicine at the UCSF Diabetes Center, the microglia senses the saturated fat and sends instructions to brain circuits in the hypothalamus. These instructions are important drivers of food intake, he said. Microglia are primarily known for causing inflammation in the brain in response to infection or injury, but the new study indicates that they also play a key role in shaping the brains response to diet, according to Koliwad. Outside the brain—in fat tissue, the liver, and muscles—other immune cells, called macrophages, trigger inflammation in response to diet-induced obesity, Koliwad said. This inflammation is implicated in triggering insulin resistance, a late stage event on the road to type 2 diabetes. When the researchers fed mice a diet high in saturated milk fats, microglia, a type of immune cell, underwent a population explosion in the brain region called the hypothalamus, which is responsible for feeding behavior. For the actual abstract and then click on Full Text Article try this link; cell/cell-reports/abstract/S2211 1247(14)00972-3 Metabolic inflammation in the Mediobasal Hypothalamus (MBH) occurs more acutely in response to the steady consumption of excess saturated fat than in peripheral tissues, where it occurs in conjunction with obesity. There is interest in mitigating MBH inflammation due to this temporal primacy and because it is linked to metabolic dysregulation. Excess Saturated Fatty Acid ( SFA) consumption induced microglial activation in the Mediobasal Hypothalamus (MBH) despite controlling for total fat and caloric intake, and without increasing body weight. These data support our in vitro data, indicating that dietary SFAs directly stimulate M1 activation of MBH microglia, whereas peripheral tissue inflammation may depend, at least in part, on the presence of obesity. Accumulation of MBH microglia in mice receiving saturated fatty acids (SFA) gavage was not due to infiltrating monocytes differentiating into microglia-like cells. Instead, our data suggest that this accumulation is due to local proliferation in the Mediobasal Hypothalamus (MBH), a capacity that was inducible by depleting hypothalamic microglia using Lip-CLO or DT A recent study suggested that SFA treatment could induce cytokine secretion by cultured astrocytes However, eliminating microglia from astrocyte cultures is difficult because astrocytes produce CSF-1, a potent microglial growth factor and traces of microglia in astrocyte cultures can confound experimental results . We treated CD11b-DTR astrocyte cultures with DT and WT astrocyte cultures with Lip-CLO to eliminate all microglia. In doing so, we found that hypothalamic microglia, and not astrocytes, secrete inflammatory cytokines when directly stimulated by Saturated Fatty acids (SFAs). This finding suggests that astrogliosis in the MBH under conditions of dietary excess may be a response to signals from activated microglia and/or neurons responding to metabolic stress. Identifying such signals is a key area for exploration. On the other hand, both astrocytes and microglia responded to LPS, indicating that astrocytes can sense certain inflammatory stimuli. Indeed, astrocyte activation, for example during infection, may stimulate responses including cachexia, that are distinct from those induced by microglial activation. Moreover, emerging evidence suggests that crosstalk between M1-like microglia and astrocytes can amplify inflammatory responses and synergistically increase the production of neurotoxic factors The significance of microglia-astrocyte crosstalk in SFA-induced Mediobasal Hypothalamus (MBH) inflammation remains to be defined. Diets rich in Saturated Fat produce inflammation, gliosis, and neuronal stress in the mediobasal hypothalamus (MBH). Here, we show that microglia mediate this process and its functional impact. Although microglia and astrocytes accumulate in the MBH of mice fed a diet rich in Saturated Fatty acids (SFAs), only the microglia undergo inflammatory activation, along with a buildup of hypothalamic SFAs. Furthermore, removing microglia from mice only reduced food intake when the content of saturated fat from milk in their diets was high. It had no effect on mice fed a low-fat diet, or a diet high in other types of fat, including olive oil or coconut oil. Remarkably, depleting microglia from the MBH of mice abolishes inflammation and neuronal stress induced by excess SFA consumption, and in this context, microglial depletion enhances leptin signaling and reduces food intake. Microglia sense Saturated Fatty acids (SFAs) and orchestrate an inflammatory process in the MBH that alters neuronal function when SFA consumption is hig Beyond promoting pathology, it is intriguing to consider the potential physiological role of microglial activation and proliferation in the MBH. Microglia respond rapidly to a variety of physiological stimuli and are implicated in the acute remodeling of neuronal circuits. These factors may act in concert to remodel hypothalamic circuitry and rapidly tailor the response to dietary intake. Such remodeling may be required, for example, to reduce satiety in predatory mammals consuming a large meal after a prolonged fast or to allow newborns to thrive solely on maternal milk. If microglia help remodel neuronal circuits under such circumstances, then the MBH inflammation in obesity may reflect the hijacking of a physiological process, as is suggested for metabolic inflammation in peripheral tissues.
Posted on: Sat, 13 Dec 2014 19:54:14 +0000
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