Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

The classical role of adipocytokines is a negative feedback mechanism, providing information about bodily energy reserves to the brain, and thus controlling satiety and food intake (Campfield et al., 1995). Adipose tissue forms the largest endocrine organ of the body. After the initial description of leptin and its receptor, LEPR/OBR, with its main active isoform OBRb, there was an initial hope for a drugable pathway to counteract the increasing burden of overweight/adiposity, metabolic syndrome, and related disorders (Figure 1). Compensatory pathways and tolerance effects, however, preclude a metabolic intervention using recombinant adipocytokines in metabolic syndrome. Leptin, for example, is increased in adiposity and metabolic syndrome. Nevertheless, recombinant leptin has been approved for leptin deficiency-associated lipodystrophy in the US.Figure 1: Schematic illustration of different pathways relevant for leptin neurobiology in the context of Parkinson’s disease.ERK: Extracellular signal-regulated kinase; JAK2: Janus kinase 2; mTOR: mammalian target of rapamycin; OBR: leptin receptor; PD: Parkinson’s disease; STAT5: signal transducers and activators of transcription 5.In addition to and overlapping with their metabolic effects, there are strong links between adipocytokines and chronic inflammation (Tilg and Moschen, 2006). The established adipocytokines include leptin, ghrelin, adiponectin, resistin, and visfatin. In part, they are also secreted by peripheral immune cells. In turn, adipocytes also secrete classical cytokines, including tumor necrosis factor, interleukin-6, interleukin-1, C1q/tumor necrosis factor-related protein-3, and CC-chemokine ligand 2. Additional emerging adipokines are RBP4, Chemerin and AFABP. In obesity, macrophages infiltrate adipose tissue and create together with adipocytes an inflammatory environment and source of adipocytokines. The expression of (adipo-) cytokine receptors on peripheral immune cells may trigger complications of metabolic syndrome through immunological mechanisms (Figure 1). The classical site of expression of OBRb and other adipocytokine receptors is within the hypothalamus but has also been described in various other brain regions including the hippocampus, cerebral cortex, mesencephalon, and spinal cord (Fujita and Yamashita, 2019). Adipocytokine receptors are expressed on neurons, but also on glial cells including astrocytes, microglia/macrophages, and oligodendrocytes. The central nervous system effect of leptin seems to be double-edged. On the one hand, multiple lines of evidence have shown neurotrophic and neuroprotective properties (Signore et al., 2008): In different cellular neuronal models, leptin increases survival and protects from apoptosis, including neuroblastoma cells and primary mouse hippocampal and cortical neurons. In vivo murine studies demonstrating the neuroprotective effects of leptin include animal models of Parkinson’s disease (PD), acute ischemic stroke, and epilepsy. Conversely, leptin activates inflammatory cells also within the central nervous system and may fuel chronic and acute neuroinflammation. Negative effects of leptin have been described in the experimental autoimmune encephalitis mouse model of multiple sclerosis, for example. PD is coined by chronically progressive degenerative processes of susceptible neuronal populations, with a relentless stereotypical spread throughout the central nervous system. Alpha-synuclein plays a central role in the pathogenesis of PD since it is the major component of the neuropathological hallmark Lewy bodies, and since single nucleotide polymorphisms in the SNCA locus confer an increased risk of PD and pathogenic variants or copy number variations of SNCA cause monogenic PD. In addition, neuroinflammatory mechanisms play an important role in PD and may represent a target to modify the disease course (Bottigliengo et al., 2022; Tansey et al., 2022). Alpha-synuclein activates microglia in vivo as well as in transgenic and lesion models of PD, and microglial activation was also present in post-mortem studies of PD. Positron emission tomography using the mitochondrial translocator protein 18 kDa (TSPO) nuclide as a marker for microglial activation provided preliminary evidence of microglial activation during earlier stages of PD but is limited by the reduced specificity and sensitivity of this group of markers due to the broad intra- and interindividual phenotypical varieties present in prodromal as well as in advanced stages of PD. Taken the rising experimental and clinical evidence supports the origin of PD in peripheral organs and the related neuro-immune axis, while secondly propagating via the blood-brain barrier to the central nervous system driven by cellular and molecular properties of the brain-immune axis (Tansey et al., 2022). These cellular and molecular components of the innate and adaptive immune system interact with and/or are impacted by mediators of immunometabolism of which leptin among other drivers of immunometabolism (e.g., ghrelin, adiponectin, resistin, progranulin, lipocalin) potentially may gain increased recognition relevant for PD prodromal diagnosis, prevention, and treatment. In summary, a prominent role of neuroinflammation in the progression of PD is becoming evident. Several clinical trials with immunomodulators in PD are ongoing (Tansey et al., 2022). The main source of leptin is white adipose tissue cells. In addition to white adipose tissue, leptin is produced by a broad variety of non-white adipose tissue, including but not limited to the heart, stomach, skeletal muscle, and placenta. Most remarkably, leptin evokes its effects far beyond energy metabolism and regulation of food intake by shaping additional multiple biological functions such as reproduction, hematopoiesis, angiogenesis, blood pressure, bone mass, immune regulation lymphoid, and T cell system. The corresponding leptin receptor isoforms have been categorized as class I cytokine superfamily promoting their molecular function via downstream intracellular signaling pathways (JAK2, STAT5, ERK, MAPK, mTOR) (Kinfe et al., 2020). Within the brain, leptin receptors are widely distributed despite the thalamus and the hypothalamus. Other brain regions expressing leptin receptors include, but may not be limited to the cortex, hippocampus, brainstem, and cerebellum indicative for the multi-functional properties of leptin and associated mediators of immunometabolic signaling beyond regulation of energy metabolism (Weng et al., 2007). With a focus on PD pathophysiology, leptin receptors are distributed on dopaminergic neurons in the ventral tegmental area relevant for reward-associated food intake circuits and the substantia nigra pars compacta modulating motor control including locomotion (Figure 1). Findings derived from in vivo and in vitro models support the neuroprotective capabilities of leptin able to counteract neuronal cell toxicity in 1-methyl-4-phenylpyridinium PD models (Regensburger et al., 2022). Quantification of concentrations of circulating leptin in biofluids (blood, cerebrospinal fluid) depends on a variety of environmental factors such as age (especially during childhood and adolescence), physical activity, and body mass index. In PD, leptin levels are altered (decreased) during early stages and further deteriorate during disease progression. As body mass index accounts to wide intra- and inter-individual variabilities within PD patients, so can the concentrations of circulating adipocytokines. Initial weight gain (reduced physical activity) turns into weight loss in PD mainly due to neurological alterations (dysphagia, decreased gastrointestinal motility, constipation, dysfunctional gut microbiome, reduced taste/ smell and hyperkinetic motor symptoms) with increased energy expenditure (Figure 1). These neurological PD deficits in turn trigger a decline of bone/muscle mass, which negatively affects energy metabolism (Lindskov et al., 2015; Tan et al., 2018). It is noteworthy, that PD specific treatments such as deep brain stimulation or cell replacement strategies may interact with leptin and associated mediators of immunometabolic signaling (Ekraminasab et al., 2022). However, the precise mechanism of these interactions impacting weight changes in both directions and in particular interactions shaping neuronal functions by adipocytokines remains largely unknown (Regensburger et al., 2022). The therapeutic potential of adipocytokines is rapidly emerging as more and more modulators are being developed. Leptin has been of particular interest due to its involvement in different diseases, including metabolic syndrome and different types of cancer (Greco et al., 2021). Different mutants of leptin and non-leptin related peptides have been developed as potent blockers or modulators of leptin signaling pathways. Moreover, the 9F8 monoclonal antibody specifically binds to leptin receptors and thereby blocks its binding, and nanobodies hold additional potential to overcome the limitations of antibody treatment. The strategy of activation of leptin receptors, in turn, has been approved in 2014 by the Food and Drug Administration and in 2018 by the European Medicines Agency with metreleptin, a recombinant analog of human leptin for the indication of inherited or acquired lipodystrophy. With several ongoing clinical trials, more information will also be derived on potential neurological effects in patients treated over longer terms. Modulation of additional adipocytokines has mainly been achieved by recombinant peptides or antibody blocking, but their effects remain largely unknown (Recinella et al., 2020). In summary, leptin and other adipocytokines represent candidate drug targets to modulate neuroinflammation also in PD. As a systemic sensor of inflammation and adipose tissue, adipocytokines cross the blood-brain barrier and their modulation therefore directly influences levels in the central nervous system. Building on the emerging links between adipocytokines in general and specifically leptin, additional studies are required to improve our understanding of potential diagnostic and therapeutic applications (Regensburger et al., 2022). MR is a fellow of the Clinician Scientist Programme (IZKF, University Hospital Erlangen) and is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; 270949263/ GRK2162) and the BMBF funded TreatHSP consortium (01GM1905B). C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y