Jais e Bruning (2017) Hypothalamic Inflammation in Obesity and Metabolic Disease
Jais e Bruning (2017) Hypothalamic Inflammation in Obesity and Metabolic Disease
Jais e Bruning (2017) Hypothalamic Inflammation in Obesity and Metabolic Disease
Review Series
Over the last years, hypothalamic inflammation has been linked to the development and progression of obesity and its
sequelae. There is accumulating evidence that this inflammation not only impairs energy balance but also contributes to
obesity-associated insulin resistance. Elevated activation of key inflammatory mediators such as JNK and IκB kinase
(IKK) occurs rapidly upon consumption of a high-fat diet, even prior to significant weight gain. This activation of
hypothalamic inflammatory pathways results in the uncoupling of caloric intake and energy expenditure, fostering
overeating and further weight gain. In addition, these inflammatory processes contribute to obesity-associated insulin
resistance and deterioration of glucose metabolism via altered neurocircuit functions. An understanding of the
contributions of different neuronal and non-neuronal cell types to hypothalamic inflammatory processes, and delineation
of the differences and similarities between acute and chronic activation of these inflammatory pathways, will be critical for
the development of novel therapeutic strategies for the treatment of obesity and metabolic syndrome.
Cologne, Cologne, Germany. 3Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne,
Cologne, Germany. 4National Center for Diabetes Research (DZD), Neuherberg, Germany.
Over the last years, hypothalamic inflammation has been linked to the development and progression of obesity and its
sequelae. There is accumulating evidence that this inflammation not only impairs energy balance but also contributes to
obesity-associated insulin resistance. Elevated activation of key inflammatory mediators such as JNK and IκB kinase (IKK)
occurs rapidly upon consumption of a high-fat diet, even prior to significant weight gain. This activation of hypothalamic
inflammatory pathways results in the uncoupling of caloric intake and energy expenditure, fostering overeating and further
weight gain. In addition, these inflammatory processes contribute to obesity-associated insulin resistance and deterioration
of glucose metabolism via altered neurocircuit functions. An understanding of the contributions of different neuronal and
non-neuronal cell types to hypothalamic inflammatory processes, and delineation of the differences and similarities between
acute and chronic activation of these inflammatory pathways, will be critical for the development of novel therapeutic
strategies for the treatment of obesity and metabolic syndrome.
the response to satiety signals and contribute to adaptive feeding Markers of hypothalamic inflammation increase significantly
behavior (ref. 28 and Figure 1). during the first days of HFD feeding, with reactive gliosis and
Under fasting conditions AgRP-expressing neurons are acti- neuronal injury manifesting during the first week, even prior to
vated to induce feeding, to inhibit energy expenditure, and to reg- body weight gain (35).
ulate glucose metabolism (13, 14, 29). More recently, we demon-
strated that an obesity-associated increase in circulating uridine Acute effects of HFD feeding
concentrations can increase hypothalamic UDP concentrations, Regulation of energy homeostasis depends on input to the hypo-
which in turn activate AgRP neurons in a P2Y6 receptor–depen- thalamus from metabolic feedback signals such as insulin and
dent manner (30). AgRP acts as an inverse agonist of MC3R/ leptin (36). Diet-induced obesity causes activation of cytokines
MC4R and counteracts the anorectic effect of α- and β-MSH, and inflammatory pathways in the hypothalamus (37). In paral-
thereby positively regulating feeding behavior (31). AgRP neuro- lel to the early occurrence of inflammation, three days of HFD
nal activity also immediately affects peripheral glucose homeo- feeding is sufficient to significantly reduce hypothalamic insulin
stasis (32, 33). Interestingly, signals that promote feeding also sensitivity in rodents (38). Importantly, these processes precede
enhance POMC neuronal activity. Activation of the cannabinoid inflammatory events in peripheral tissues, such as the liver (39).
receptor CBR1, which is known to mediate cannabinoid-induced Several studies have shown that specific lipid species are linked
food intake, leads to the (paradoxical) activation of POMC neu- with resistance to the main adipostatic hormones insulin and leptin
rons and the selective release of β-endorphin instead of α-MSH in peripheral tissues (40–43). Fatty acids, especially long-chain sat-
(34). This preferential production of β-endorphin is dependent on urated fatty acids (SFAs), can acutely modulate neuronal control of
endocannabinoid receptor expression in mitochondria and modu- energy homeostasis. Enteric gavage with SFAs induces hypotha-
lation of mitochondrial uncoupling protein 2. lamic inflammation within days, whereas administration of mono-
In this context it is remarkable how rapidly overconsump- unsaturated fatty acids did not result in compromised hypothalam-
tion of a fat-rich diet results in acute changes in the feedback to ic function (44). SFAs, such as palmitate and stearate, are able to
metabolic endocrine signals (such as leptin and insulin signaling) cross the blood-brain barrier (BBB) and accumulate specifically
and in hypothalamic inflammatory responses (35). Inflammatory in the hypothalamus, where they blunt anorexigenic signaling by
processes in the hypothalamus occur in two phases. A transient, insulin and leptin and thereby promote positive energy balance
early inflammatory phase and, with sustained exposure to high- (44–46). SFAs, unlike unsaturated fatty acids, trigger the activation
fat diet (HFD), a secondary phase, in which prolonged inflamma- of inflammatory signaling cascades via TLR4 signaling and the
tory cascades lead to the activation of cellular stress mechanisms. adaptor molecule myeloid differentiation primary response gene
such as ketone bodies during development and starvation (92). fed regular chow (113). These findings imply that increased expo-
Glucose is primarily taken up by astrocytes located around blood sure to dietary lipids, but not increased body weight, is the pre-
vessels and metabolized to lactate, which is supplied to neurons dominant driver of BBB impairment. Furthermore, mice that are
(93). However, a recent study is challenging this view and shows fed a long-term HFD show increased hypothalamic angiopathy
that neurons, and not astrocytes, are the primary consumers of with increased blood vessel density and length (102).
glucose (94). Apart from this shuttling function, astrocytes play a
key role in maintaining synaptic plasticity and survival (95). Contributions of other cell types
HFD is associated with the accumulation and activation of Tanycytes are specialized glial cells that play a crucial role in the
astrocytes in the hypothalamus (35, 96). Reactive astrocytosis in transport of and response to leptin (112, 114). These cells have long
the hypothalamus occurs as early as 24 hours after HFD intake processes that bridge the cerebrospinal fluid to the portal capil-
(97). In response to HFD feeding, hypothalamic astrocytes pro- laries. Recently another cell type, NG2-glia cells (also known as
duce a variety of inflammatory factors. Again, SFAs activate oligodendrocyte precursors) were determined to be critical for
inflammatory signaling pathways in primary astrocyte cultures hypothalamic function, as the ARC leptin receptor neurons lose
and trigger the release of inflammatory cytokines (98). Astrocytes responsiveness to leptin after NG2-glia ablation (115). These cell
also express TLRs that respond to inflammatory triggers via acti- types are part of a complex regulatory network involved in main-
vation of the NF-κB pathway, which in turn regulates the expres- tenance of metabolic homeostasis and underscore the importance
sion of proinflammatory cytokines (99). In addition, obesity- of understanding the interactions between neuronal and non-neu-
induced production of TGF-β by astrocytes induces a hypothalam- ronal cells in hypothalamic inflammation.
ic RNA stress response to accelerate Ikba mRNA decay, leading to
atypical NF-κB activation in the hypothalamus (100). Thus, cross- Hypothalamic deregulation in the human brain
talk of astrocytes and neurons in response to HFD intake plays a There is growing evidence that consumption of a high-fat, high car-
fundamental role in hypothalamic inflammation. bohydrate diet is associated with hypothalamic deregulation in the
human brain, but so far only a few studies have addressed anoma-
Hypothalamic vasculature and the BBB lous hypothalamic function in the human brain directly. A retrospec-
Alterations of the BBB are fundamentally involved in the devel- tive analysis of MRIs of non-obese and obese patients showed evi-
opment of hypothalamic inflammation (101). The BBB acts as dence of increased gliosis in the MBH of obese humans (35). A study
an interface between the CNS and peripheral tissues, regulating using diffusion tensor imaging reported obesity-associated hypo-
the exchange of substances between the circulation and the brain thalamic damage associated with inflammatory markers and worse
parenchyma. Pathologic changes in the hypothalamic vasculature cognitive performance (116). Furthermore, obesity-related systemic
have been observed in response to a HFD/high-sucrose diet in inflammation reduces the integrity of brain structures involved in
rodents as well as in patients with type 2 diabetes (102). Moreover, reward and feeding behaviors (117). Mouse models of obesity pro-
the unique, fenestrated capillary system in the median eminence vide unique insights into disease mechanisms but have their trans-
exposes hypothalamic cell populations to stress-promoting signals lational limitations, as exemplified by the lack of β-MSH in mice
emanating from peripheral circulation (35, 103, 104). Interesting- (27). In light of the limited knowledge of metabolic inflammation in
ly, obesity-associated astrogliosis does not occur uniformly across the human brain, further neuroimaging studies on human patients
the hypothalamus, but is associated with microvessels, suggesting are needed to validate findings from animal models and potential
a possible response by astrocytes to changes at the BBB and/or therapeutic strategies. Neuroimaging techniques such as functional
the peripheral circulation (105). IL-1β is upregulated in the CNS MRI, PET, electroencephalography, and magnetoencephalography
during HFD feeding and contributes to BBB dysfunction via the are powerful tools for directly investigating changes in brain func-
transcriptional repression of claudin-5 (106), a tight junction pro- tion associated with human obesity and provide an important link
tein critically involved in maintaining BBB integrity (107). Further- between animal studies and clinical research in obese patients.
more, long-term intake of a hypercaloric diet decreases expres-
sion of other tight junction proteins on brain endothelial cells and Hypothalamic inflammation and deregulation
increases in microgliosis (108). This disruption of BBB integrity of peripheral tissues
permits leukocyte infiltration into the brain (109). Critically, the Hypothalamic neurons project to autonomic sites such as the ros-
function of the BBB is controlled by VEGF, which is the key regu- tral ventrolateral medulla, NTS, and dorsal motor nucleus of the
lator of neovascularization, blood vessel homeostasis, and hyper- vagus nerve in the hindbrain (118, 119). The sympathetic nervous
vascularization (110). Recently, work from our lab has shown that system stimulates thermogenesis and stabilizes body weight via
acute HFD feeding leads to reduced brain glucose uptake. Sub- activation of β-adrenergic receptors. HFD-induced hypothalamic
sequent activation of perivascular macrophages increases VEGF inflammation disrupts this regulatory pathway of energy homeo-
production, which is sufficient to reconstitute glucose transporter stasis. Overnutrition is associated with excessive sympathoexci-
expression at the BBB (91). Long-term HFD feeding results in the tation, which increases weight gain as a consequence of reduced
expression of VEGF in astrocytes (111) as well as in tanycytes in sensitivity of β-adrenergic receptors (120). In this context, NF-κB–
the hypothalamus (112), which promotes microvessel permeabili- mediated inflammation in POMC neurons, rather than AgRP
ty and disruption of BBB integrity. HFD-fed mice show increased neurons, is required for overnutrition-induced sympathoexci-
accumulation of IgG in the ARC, whereas in chow-fed obese ob/ob tation (121). Furthermore, a reduction in parasympathetic tone
mice, IgG deposition was comparable to control wild-type mice has been demonstrated to contribute to the activation of inflam-
matory responses in obesity (122, 123). Activation of α7 nicotinic bidities. Most of the evidence points to uncoupling of food intake
acetylcholine receptors on immune cells could thus limit obesi- and energy expenditure due to diet-induced inflammation and
ty-induced inflammation and subsequently improve systemic gliosis in the hypothalamus. Obesogenic diets elicit early inflam-
insulin resistance (124, 125). Hypothalamic inflammation exerts matory effects in the hypothalamus, which precede inflamma-
broad effects on peripheral tissues, such as modulation of insulin tory events in peripheral tissues. Metabolic processes are not
secretion by pancreatic β cells (83). Similar to β cells (126), glucose regulated via neuronal cells alone, but rather they are embedded
sensing in POMC neurons is lost during the development of met- in a complex regulatory system of different cell types. Prolonged
abolic syndrome, which subsequently leads to impaired control over-nutrition leads to sustained hypothalamic inflammatory
of glucose metabolism and energy homeostasis (127). In rodents, processes via interactions between neurons and non-neuronal
three days of HFD feeding were sufficient to impair the ability of cell populations, perpetuating these initially reversible process-
hypothalamic insulin to suppress white adipose tissue lipolysis es and ultimately resulting in uncoupling between caloric intake
and hepatic glucose production (128). In addition, hypothalamic and energy expenditure, fostering overeating and further weight
inflammation leads to deregulation of peripheral insulin action gain. Understanding the contributions of different neuronal and
(129) and a reduction in adaptive thermogenesis (130, 131). non-neuronal cell types to hypothalamic inflammatory processes
and delineating differences and similarities between acute and
Maternal metabolic imprinting chronic activation of inflammatory pathways will be critical to
Increasing evidence from human and animal studies suggests that the development of novel therapeutic strategies for the treat-
maternal obesity and/or diabetes has long-term consequences ment of metabolic syndrome.
for the future health of offspring (132–135). Maternal feeding of
a HFD only during lactation impairs hypothalamic melanocortin Acknowledgments
circuitry, leading to malformation of neural projections as a con- The authors apologize to all authors not cited who have made
sequence of abnormal insulin signaling (134). The maternal diet important contributions. This work was supported by a grant from
affects hypothalamic function and plasticity, resulting in alter- the DFG (BR 1492/7-1) to JCB, by the DFG-funded TRR134 collab-
ations to energy homeostasis in the offspring. Furthermore, HFD orative research center, and by the CMMC and the Excellence Ini-
exposure prior to and during pregnancy in rodents (136, 137) and tiative by German Federal and State Governments (CECAD). The
non-human primates (138, 139) leads to activation of the maternal authors were supported in part by the Helmholtz Alliance Imaging
immune system and subsequent increases in brain inflammatory and Curing Environmental Metabolic Diseases (ICEMED), through
markers of the offspring. Therefore, inflammatory pathways in the the Initiative and Networking Fund of the Helmholtz Association.
brain may already be primed toward a proinflammatory response The authors also received funding from the European Union Sev-
as a consequence of maternal diet. enth Framework Program (FP7/2007-2013) under grant 266408.
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