TEM 1264 No.

of Pages 11

Review

JAK/STAT – Emerging Players in Metabolism

David W. Dodington,1 Harsh R. Desai,1 and Minna Woo1,2,*

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) Trends
pathway is crucial for transducing signals from a variety of metabolically The JAK/STAT signaling pathway
serves as an important downstream
relevant hormones and cytokines including growth hormone, leptin, erythro-
mediator for a variety of cytokines, hor-
poietin, IL4, IL6 and IFNg. A growing body of evidence suggests that this mones, and growth factors. Emerging
pathway is dysregulated in the context of obesity and metabolic disease. data show that this pathway is dysre-
gulated in metabolic diseases includ-
Recent development of animal models has been instrumental in identifying ing obesity and type 2 diabetes.
the role of JAK/STAT signaling in the peripheral metabolic organs including
adipose, liver, muscle, pancreas, and the immune system. In this review we With the use of tissue-specific knock-
out mice, JAK/STAT signaling in the
summarize current knowledge about the function of JAK/STAT proteins in the peripheral metabolic organs has been
regulation of metabolism, and highlight new potential therapeutic targets for shown to regulate a multitude of meta-
bolic processes including, but not lim-
the treatment of obesity and diabetes.
ited to, glucose tolerance, insulin
sensitivity, energy expenditure, and
JAK/STAT Pathway at a Glance adiposity.

The JAK/signal transducer and activator of transcription (STAT; see Glossary) pathway is JAK/STAT signaling within immune
one of the major intracellular signal transduction pathways that serves as an important cells crucially regulates inflammation
downstream mediator for various cytokines, hormones, and growth factors (Figure 1). JAK that is associated with metabolic
proteins are recruited to the intracellular domains of various receptors upon binding of their abnormalities including insulin resis-
tance and obesity.
cognate ligand, where they are dimerized and activated through autophosphorylation. These
activated JAKs in turn phosphorylate and activate STAT proteins, which themselves dimerize The JAK/STAT signaling pathway is a
and translocate to the nucleus where they regulate gene transcription. Four members of the promising therapeutic target for the
JAK family have been identified in mammals: JAK1, JAK2, JAK3, and TYK2, and seven treatment of obesity, metabolic syn-
drome, and diabetes.
members of the STAT family: STAT1–4, STAT5A/B, and STAT6. Depending on the cytokine
or growth factor signal, different combinations of JAKs and STATs are activated with a high
degree of specificity. JAK/STAT proteins are ubiquitously expressed and are involved in the
regulation and maintenance of a range of fundamental biological processes including apopto-
sis, proliferation, the immune response, and inflammation [1].

Current State of the Clinical Use of JAK and STAT Inhibitors

Dysfunction of the JAK/STAT pathway has been implicated in various pathologies including
hematologic malignancies and autoimmune diseases, for which JAK inhibitors show promising
effect. To date, ruxolitinib, a JAK1/2 inhibitor, has been approved for the treatment of
myelofibrosis, and the JAK1/3 inhibitor, tofacitinib, has been approved for the treatment
of rheumatoid arthritis [2,3]. JAK inhibitors are also in clinical trials for diabetic nephropathy, 1
Toronto General Hospital Research
Crohn’s disease, ulcerative colitis, psoriasis, atopic dermatitis, and systemic lupus erythema-
Institute, University Health Network,
tosus [4]. The increasing investigation of JAK inhibitors stems from our growing understanding Toronto, M5G 1L7, Canada
2
of this crucial pathway and its role in disease. Continued elucidation of the role of individual JAK/ Division of Endocrinology and
Metabolism, Department of Medicine,
STAT proteins in different cell types will enable more specific therapeutic design to target
University Health Network and
pathological mechanisms while minimizing undesired side effects. University of Toronto, Toronto, M5G
2C4, Canada
Implications of the JAK/STAT Pathway in Obesity and Metabolic Disease
In recent years the JAK/STAT pathway has been implicated in the pathogenesis of metabolic *Correspondence:
disease by both clinical and basic science research. In population studies, some mwoo@uhnresearch.ca (M. Woo).

Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.tem.2017.11.001 1
© 2017 Elsevier Ltd. All rights reserved.
 TEM 1264 No. of Pages 11

Figure 1. Schematic of JAK/STAT Glossary

Cytokine or Signaling. The Janus kinase (JAK)/signal
growth factor Acinar cells: exocrine cells of the
transducer and activator of transcription
Plasma membrane receptor pancreas which produce enzymes
(STAT) signaling pathway is activated by a
that assist in the digestion of food.
wide variety of cytokines and growth fac-
JAK JAK tors. Binding of the ligand to its receptor
Adiponectin (APN): a hormone
Cytoplasm P P secreted by adipose tissue that
activates JAK proteins. Activated JAKs
P P regulates energy homeostasis.
self-phosphorylate and phosphorylate
Adipocyte protein 2 (AP2): a
(P) their associated receptor. This recruits
P P carrier protein for fatty acids that is
the STAT family of transcription factors;
expressed primarily in adipocytes
STAT STAT these are phosphorylated by JAKs,
and macrophages.
resulting in homo- or hetero-dimerization
Brown adipose tissue (BAT): a
of STAT proteins and translocation to the
type of adipose tissue that functions
nucleus where they bind to response ele-
STAT to convert chemical energy into heat.
P ments on DNA and modulate transcrip-
b Cell: a cell within the pancreatic
P tion of downstream target genes.
islet that produces, stores, and
STAT
secretes the hormone insulin.
Ciliary neurotrophic factor
(CNTF): a protein that promotes
Nucleus
neurotransmitter synthesis and
STAT
P neurite outgrowth.
Gene
P Epidermal growth factor (EGF): a
STAT expression
mitogenic factor for cell growth,
proliferation, and differentiation.
Erythropoietin (EPO): a hormone
produced by the kidney that
promotes the formation of red blood
cells by the bone marrow.
Glucose intolerance: impaired
polymorphisms in the JAK2 gene have been associated with central adiposity and increased ability to properly dispose glucose,
waist circumference [5], while others are linked to a reduced risk of metabolic syndrome [6]. leading to elevated levels in
In addition, a polymorphism in the STAT5B binding site of the PPARG3 (peroxisome pro- circulation.
Gluconeogenesis: a metabolic
liferator-activated receptor g) gene promoter has been associated with an increase in
pathway that results in the
plasma low-density lipoprotein cholesterol concentrations [7]. These studies suggest that generation of glucose from non-
perturbations in the JAK/STAT signaling pathway may have significant metabolic effects in carbohydrate carbon substrates.
humans. Growth hormone (GH): a hormone
that stimulates cell growth,
proliferation and regeneration.
Mouse models have been instrumental in delineating the metabolic role of JAK/STAT signaling Insulin-like growth factor 1
in vivo (Table 1). While whole-body deletion of Jak1 or Jak2 leads to neonatal or embryonic (IGF1): a hormone with a similar
lethality, mice with global deficiency of Jak3 are viable but display several features of insulin structure to insulin that functions in
growth, development, and
resistance, including increased body weight and fasting insulin and glucose levels, as well as
metabolism.
glucose intolerance and liver steatosis [8]. Similarly, mice lacking Tyk2 are prone to obesity Insulin resistance: a pathological
and impaired glucose tolerance [9], and mice lacking Stat6 display glucose intolerance, insulin condition in which cells fail to
resistance and hepatic steatosis [10]. By contrast, ablation of Stat4 results in reduced adipose respond physiologically to insulin.
Interferon (IFN): a cytokine involved
tissue inflammation and improved insulin sensitivity in diet-induced obesity [11]. in the immune response and
inflammation.
The development of tissue-specific Jak/Stat knockout (KO) mice has been instrumental in Interleukin (IL): a cytokine involved
elucidating the role of this pathway in the various metabolic organs. Cumulative evidence in the immune response and
inflammation.
demonstrates that the role of any given JAK/STAT protein in metabolism is highly context- Leptin: a hormone predominantly
dependent and cell type-specific. JAK/STAT signaling has crucial functions in metabolically made by adipose tissue that
active tissues including adipose, liver, skeletal muscle, and pancreatic b cells, as well as in regulates energy balance.
Metabolic syndrome: a cluster of
immune cells including macrophages, natural killer cells, and T cells. Specific disruption of
conditions that increase the risk of
JAK/STAT signaling in these tissues can lead to various metabolic derangements or, in some cardiovascular disease including
cases, protection from obesity and its associated perturbations. In this review we summarize central abdominal obesity, high blood
the role JAK/STAT signaling in the various peripheral metabolic organs and its impact on pressure, high blood sugar, high
metabolic homeostasis with a focus on recently developed in vivo models.

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Table 1. Mouse Studies Targeting the JAK/STAT Signaling Pathway and Their Effects on Obesity and serum triglycerides, and low high-
Metabolisma density lipoprotein (HDL) levels.
Myelofibrosis: a type of chronic
Tissue (Cre line) Gene Diet Phenotypeb Refs
leukemia in which extensive scarring
Whole body Jak3 ND/HFD "BW, "FBG, "AD, #GT, "HS [8] in the bone marrow disrupts normal
production of blood cells. Activating
Tyk2 ND "BW, #GT, #EE, #BAT [9]
JAK2 mutations are found in this
Stat4 HFD BW, AD, "GT, "IS, #ATI [11] condition.
Non-obese diabetic (NOD)
Stat6 HFD #BW, #AD, #GT, #IS, "EE, "HS [10]
mouse: a strain of mice that develop
Adipose (Apn) Jak2 ND/HFD BW, "AD, #FBG, "IS [12,14] spontaneous autoimmune pancreatic
b-cell destruction that is used as a
Stat5 ND BW, "AD, "IS [16]
model of type 1 diabetes.
Adipose (Ap2) Jak2 ND/HFD "BW, "AD, #EE, #GT, #IS (females) [13,18] Pancreatic and duodenal
homeobox 1 (PDX1): a transcription
Stat3 ND "BW (males), "AD,"BAT, EE, GT, "HS [15]
factor necessary for pancreatic
Liver (Alb) Jak2 ND/HFD #BW, #AD, "HS, "TG, "FFA, "cholesterol [29,30] development.
Peroxisome proliferator-activated
Stat3 ND/HFD "BW, GT, "RBG, #IS, "gluconeogenesis [21,22]
receptors (PPARs): a group of
Stat5 ND BW, "AD, "RBG, "TG, #GT, #IS, "HS [31,32] transcription factors that regulate
genes important for development
Liver (Ttr) Stat3 ND BW, AD, "FBG, RBG, #GT, #IS [23]
and metabolism.
Muscle (Mck) Stat3 HFD BW, AD, EE, GT [50] Prolactin: a hormone secreted by
Muscle (Myf5) Stat5 ND #Size, AD, #lean mass, FBG, #GT, IS [44] the pituitary gland that promotes
lactation.
Stat5 ND #BW, #muscle mass, #EE [45] Rat insulin promoter (RIP): DNA
Stat5 HFD BW, #muscle, AD, "FBG, "FFA, "TG, "HS [46] sequence that regulates the
expression of insulin in rats and
b Cells (RIP) Jak2 ND/HFD BW, FBG, GT, IR, b cell mass [54] mice.
Stat3 ND "BW, "AD, #GT, "FBG, b cell mass [55,56] Signal transducers and activators
of transcription (STAT): intracellular
Stat5 ND BW, "AD, "FBG, "FFA, #GT [65] transcription factors that are primarily
Stat5 DN HFD "BW, "FBG, #GT [64] activated by membrane receptor-
Stat5 CA HFD BW, FBG, "GT associated Janus kinases (JAKs).
Steatosis: the abnormal retention of
b Cells (Pdx1) Stat3 ND BW, #GT, IS, #GSIS, altered architecture [57,58] lipids within a cell.
Stat5 ND BW, FBG, #GT [65] T cells: a type of immune cell that
plays a role in the adaptive immune
Myeloid (Lysm) Jak2 HFD BW, AD, GT, "IS, #ATI, #CLS [73] system.
NK cell (Ncr1) Stat3 HFD #BW, #AD, #HS, #ATI, "GT, "IS [77] Transthyretin (TTR): a transport
protein, synthesized by the liver, that
T cell transfer Stat4 HFD BW, "GT, IS, #ATI, #CLS [78] carries the thyroid hormone thyroxine
and retinol-binding protein.
a
Symbols: ", increased; #, decreased; , no change.
b Uncoupling protein (UCP): a
Abbreviations: AD, adiposity, Apn, adiponectin; Alb, albumin; Ap2, fatty acid binding protein 2/adipocyte protein 2;
ATI, adipose tissue inflammation, BAT, brown adipose tissue; BW, body weight; CA, constitutively activated; CLS, crown- mitochondrial inner membrane
like structures; DN, dominant negative; EE, energy expenditure; FBG, fasting blood glucose; FFA, free-fatty acid; GT, protein that is responsible for
glucose tolerance; GSIS, glucose-stimulated insulin secretion; HFD, high-fat diet; HS, hepatic steatosis; IS, insulin converting energy to heat instead of
sensitivity; Lysm, lysozyme M; Mck, muscle creatine kinase; Myf5, myogenic factor 5; Ncr1, natural cytotoxicity triggering ATP.
receptor 1; ND, normal chow diet; NK, natural killer; Pdx1, pancreatic and duodenal homeobox 1; RBG, random blood White adipose tissue (WAT): the
glucose; RIP, rat insulin promoter; Ttr, transthyretin. major site of energy storage in the
form of fat, contributes to endocrine
regulation of energy balance.
Adipose Tissue
Adipose tissue is one of the master regulators of energy balance and fuel homeostasis. There
are two main types of adipose tissue: white adipose tissue (WAT), which serves as a major
energy storage depot, and brown adipose tissue (BAT), which functions to dissipate stored
energy in the form of heat. Insulin resistance in WAT and dysfunctional lipid storage are sentinel
events in the progression of metabolic syndrome and type 2 diabetes (T2D).

JAK2, STAT3, and STAT5 are necessary for signaling through both the growth hormone (GH)
and leptin receptors, and have been well characterized in WAT. Adipose-specific Jak2 KO

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mice have impaired lipolysis in response to growth hormone and leptin, resulting in greater
weight gain and adiposity, even on a control chow diet [12–14]. Similarly, loss of either Stat3
[15] or Stat5 [16] in adipose tissue results in significant weight gain, adiposity, and impaired
lipolysis. These defects arise primarily due to impaired expression of essential lipolytic genes in
WAT. Some controversy exists on the effects of adipocyte JAK2/STAT5 on insulin sensitivity
because some studies report insulin resistance [13] while others report increased whole-body
insulin sensitivity in the absence of JAK2 or STAT5 [12,14]. In the case of enhanced insulin
sensitivity in the absence of adipocyte JAK2, this may in part be due to a reduction in fatty acid-
induced hepatic insulin resistance, but alternative mechanisms are also thought to exist [12].
Overall, these discrepancies may be due to a variety of factors including tissue-specificity and
cell stage-dependent expression of the cre transgene, mouse genetic background, physiologic
status (age, sex, diet), and other environmental factors in which the experiments were con-
ducted [17].

In addition to its role in WAT, JAK/STAT signaling has been implicated in the function of BAT. In
mice, JAK2 is highly expressed in BAT compared to WAT, and JAK2 is further upregulated in
response to high-fat diet (HFD) feeding [18]. JAK2 has also been shown to be crucial for the
induction of uncoupling protein 1 (UCP1) in BAT and the increase in energy expenditure in
response to adrenergic stimulus, cold exposure, and HFD feeding. Similarly, TYK2 has been
reported to play an essential role in BAT development in mice [9]. TYK2 expression is down-
regulated during HFD-induced obesity, and whole-body Tyk2 KO mice display loss of BAT
lineage cells, which can be rescued by expression of a constitutively active STAT3 protein in
preadipocytes [9]. In contrast to these in vivo mouse studies, an in vitro pharmacological
screening study found that the JAK1/3 inhibitor, tofacitinib, induced ‘browning’ (increased
UCP1 expression and altered lipid morphology) in human adipocytes, which was dependent on
suppression of interferon (IFN) signaling and activation of hedgehog signaling [19]. The in vivo
implications of this, however, are currently unknown. Thus, further research on JAK/STAT
signaling in BAT holds great promise for discovery of novel therapeutic agents to induce
adipocyte ‘browning’ in vivo, with significant potential for the treatment of obesity.

Liver
The liver is an important metabolic organ that regulates both glucose and lipid homeostasis.
With hepatic insulin resistance, there is inadequate suppression of gluconeogenesis,
which can contribute to the development of hyperglycemia and hepatic steatosis [20]. Multiple
JAK/STAT pathways have been implicated in hepatic function including the interleukin
6 (IL6)–STAT3 axis, the GH–JAK2–STAT5–insulin-like growth factor 1 (IGF1) axis, and
the IL4–STAT6 axis.

Studies have consistently demonstrated that hepatocyte-specific deficiency of STAT3 leads to

insulin resistance and increased expression of gluconeogenic genes, at least partly through
disruption of IL6 signaling [21–24]. This is consistent with the finding that IL6-deficient mice
develop hepatosteatosis and insulin resistance during HFD feeding [25]. In addition, STAT3 has
been shown to be activated downstream of IL13 in hepatocytes, which is also responsible for
suppressing hepatic gluconeogenesis, demonstrating that STAT3 integrates multiple signals in
the regulation of hepatic glucose metabolism [26]. Not surprisingly then, expression of a
constitutively active STAT3 in hepatocytes in obese mice has been shown to suppress
gluconeogenic gene expression and reduce hyperglycemia [21].

Various groups have also demonstrated the pivotal role of the hepatic GH–JAK2–STAT5–IGF1
axis in lipid metabolism. In the liver, targeted deletion of the genes encoding GH receptor

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[27,28], JAK2 [29,30], or STAT5 [31,32] leads to profound lipid accumulation and hepatic
steatosis with hepatic or systemic insulin resistance, which has been explained by two
proposed mechanisms. First, disruption of the GH signaling axis leads to increased flux of
free fatty acids (FFA) to the liver by upregulation of the fatty acid transporter CD36. Thus,
deletion of Cd36 can rescue the fatty liver observed in Stat5 KO mice [32]. Second, there is an
increase in de novo lipogenesis observed in adult-onset GH receptor KO mice [33,34]. This was
initially thought to be due to increased expression of PPARg, but has recently been shown to be
independent of PPARg [34]. In addition, disruption of hepatic IGF1 expression has been a
proposed mediator of the metabolic effects of GH signaling deficiency. Reduced circulating
IGF1 concentrations lead to an increase in circulating GH due to loss of negative feedback,
resulting in increased lipolysis and liberation of FFA from adipocytes [29]. Interestingly, resto-
ration of IGF1 in hepatic GH receptor-deficient mice is not sufficient to protect against steatosis,
indicating direct effects of GH on lipid uptake and de novo lipogenesis independently of IGF1
[35]. Studies in humans also support a role for GH in the development of hepatic steatosis
because isolated GH deficiency [36] or lower GH levels in normal subjects [37] have been
associated with increased prevalence of non-alcoholic fatty liver disease.

Another JAK/STAT pathway that may be important in hepatic metabolism is the IL4–STAT6
pathway, which has been shown to promote glucose oxidation over fatty acid oxidation by
inhibiting PPARa activity in hepatocytes [10]. Genetic ablation of STAT6 also promotes hepatic
steatosis and insulin resistance; however, this was demonstrated in whole-body Stat6 KO
mice, and thus it is difficult to determine if the observed phenotype is attributed to liver STAT6
deficiency per se.

Together, these studies demonstrate that JAK/STAT signaling is crucial for a variety of
metabolic functions of the liver. Disruption of JAK/STAT signaling pathways can result in
dysregulation of hepatic glucose production, hepatic steatosis, and insulin resistance. There-
fore, based on our current knowledge, therapeutic strategies for metabolic disease should aim
to preserve or optimize JAK/STAT signaling in the liver.

Skeletal Muscle
Skeletal muscle, as the predominant site of postprandial glucose uptake and essential for
physical activity, is a crucial regulator of energy metabolism and glucose homeostasis. In
obesity and diabetes there is loss of muscle mass, intracellular lipid accumulation, and
decrease in muscle insulin sensitivity [38]. As in the liver, JAK/STAT proteins are necessary
for transducing signals by GH and IL6.

Although the role of GH in postnatal growth is well documented, the specific action of GH on
skeletal muscle is yet to be fully understood. It was initially reported that muscle-specific
deletion of Ghr in mice using the Mef2c promoter, which is expressed at embryonic (E) day
E7.5, results in impaired muscle development by decreasing myocyte fusion and is associ-
ated with increased adiposity, insulin resistance, and glucose intolerance [39]. Subsequently,
studies targeting the GHR using the muscle creatine kinase (Mck) promoter, which is
expressed postnatally, found that loss of GHR did not alter muscle mass or fiber type
[40] and actually reduced adiposity and improved insulin sensitivity [41,42]. These changes
in adiposity may be due to increased lipid oxidation during exercise and increased lipolysis of
adipose tissue during fasting [43]. Thus, the effects of GH on skeletal muscle are likely
dependent on the specific model used and the stage of development at the time the genetic
disruption occurred.

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Muscle-specific deletion of Stat5 using the Myf5 promoter leads to decreased lean body mass
and glucose intolerance on chow diet [44,45]. When placed on a HFD, STAT5 deficiency leads
to increased accumulation of lipid in skeletal muscle, dyslipidemia, hepatic steatosis, and
hyperglycemia [46]. These defects in skeletal muscle mass appear to be due to both loss of
local/autocrine production of IGF1 as well as to impaired GH-stimulated androgen receptor
expression in skeletal muscle, which is necessary for growth. In addition, there is altered
expression of genes involved in lipogenesis, lipid uptake, lipolysis, insulin signaling, and glucose
uptake, suggesting that direct effects of STAT5 on gene expression are crucial for regulation of
lipid and glucose metabolism [46].

IL6–JAK2–STAT3 signaling in skeletal muscle has been examined in humans with T2D, and
may have a pathogenic role in the development of inflammation and insulin resistance.
Phosphorylated JAK2 and STAT3 are increased in skeletal muscle biopsies from individuals
with impaired glucose tolerance or T2D, and phosphorylated STAT3 levels correlate with
measures of insulin resistance such as HOMA-IR (homeostatic model assessment of insulin
resistance) [47,48]. In vitro, it was shown that IL6-induction of Toll-like receptor 4 via STAT3
leads to expression of proinflammatory cytokines and insulin resistance in human skeletal
muscle myoblasts [48]. There is also evidence to suggest that individuals with T2D develop IL6
resistance because the ability of IL6 to induce glycogen synthesis and glucose uptake in
skeletal muscle is lost in the setting of T2D [49]. Interestingly, muscle-specific Stat3 KO mice do
not show any changes in insulin sensitivity compared to wild-type controls even after HFD
feeding [50]. One caveat is that the mice were on an HFD for only 3 weeks, which may not be
sufficient to induce metabolic changes.

Other JAK/STAT signaling pathways have also been implicated in skeletal muscle metabolism
but have so far only been investigated in vitro. For example, IL15, a myokine released from
skeletal muscle during exercise, signals through JAK3/STAT3, resulting in translocation of
GLUT4 to the plasma membrane that mediates glucose uptake [51]. The proinflammatory
cytokine, IFNg, can also signal through STAT1 in myocytes to cause insulin resistance [52].

These studies demonstrate the wide array of metabolic functions mediated by JAK/STAT
signaling in skeletal muscle. While disruption of STAT5 may lead to adverse metabolic con-
sequences through deregulated GH signaling, targeting STAT3 in skeletal muscle may atten-
uate IL6-induced insulin resistance. However, both of these pathways require further
investigation to fully elucidate their role at different timepoints during muscle development.
A variety of other potential JAK/STAT pathways activated in skeletal muscle also warrant further
investigation in vivo, and may have therapeutic potential in metabolic disease.

Pancreas
The pancreatic islets play a crucial role in glucose homeostasis as the source of insulin and
other glucose-modulating hormones. The pancreatic b [375_TD$IF]cells are themselves responsive to
insulin, as well as to various other hormones, growth factors, and cytokines including IFN-g,
GH, prolactin, and erythropoietin (EPO), which are dependent on JAK/STAT signaling. As
such, JAK2, STAT3, STAT5, and STAT1 have each been investigated for potential relevance in
both T1D and T2D models.

EPO is well known for its role in stimulating red blood cell production but also has extra-
hematopoietic functions. Administration of exogenous EPO in rodent models of T1D and T2D
reverses hyperglycemia through direct effects on pancreatic b cells and expansion of b cell
mass [53]. The beneficial effects of exogenous EPO are dependent on both b cell-specific

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EPO-receptor and JAK2 expression; however, ablation of genes encoding either the EPO-
receptor or JAK2 in pancreatic b cells does not significantly alter their mass or glucose
homeostasis under basal conditions [53,54]. These data suggest that, while EPO–JAK2
signaling does not have an essential developmental or homeostatic role, enhancing this
pathway, as in the case of exogenous EPO, can have pharmacologic cytoprotective role in
models of diabetes.

Disruption of Stat3 in pancreatic b cells leads to hyperglycemia, glucose intolerance, increased

appetite, and weight gain [55,56]. These findings however are attributed to rat insulin
promoter (RIP)2 in driving Stat3 deletion in the hypothalamus in addition to the pancreatic
b cells. When the studies were repeated using the pancreas-specific Pdx1 (pancreatic and
duodenal homeobox 1) promoter, loss of STAT3 only resulted in aberrant islet architecture,
glucose intolerance and impaired insulin secretion in vivo, but with normal insulin secretion in
size-matched islets ex vivo [57,58]. This suggests that, although STAT3 is essential in the
development of proper islet architecture, it is dispensable for the function of mature islets.
STAT3 is also shown to be essential in the response to exogenous epidermal growth factor
(EGF) and ciliary neurotrophic factor (CNTF) in reprogramming pancreatic acinar cells into
insulin secreting ‘b-like’ cells, which can restore normoglycemia in diabetic mice [59]. Similar
results have been obtained in human exocrine pancreas cells in vitro, where reprogramming of
acinar cells into ‘b-like’ cells was achieved through expression of a constitutively active STAT3
[60].

GH and prolactin each have important roles in islet biology. GH is crucial in mediating glucose-
stimulated insulin secretion as well as b cell hyperplasia in response to HFD [61], while prolactin
is essential for expansion of b cell mass during pregnancy [62]. Signaling by GH and prolactin is
dependent on the activation of STAT5 [63]. Generation of Stat5 KO mice using the Rip2
promoter results in a variety of metabolic defects, however this is likely due to hypothalamic
expression of Cre recombinase [64,65]. Upon targeting STAT5 with the Pdx1 promoter,
pancreas-specific Stat5 KO mice show normal islet formation but develop mild glucose
intolerance with aging, suggesting an essential role of STAT5 in mature islet function [65].
This may be explained by the fact that STAT5 is a potent inducer of insulin gene expression in
vitro [66].

STAT1, which is required for IFNg signaling, is implicated as a potential therapeutic target in
models of T1D. STAT1 is overexpressed in islets from individuals with T1D and is strongly
correlated with HLA class I expression in b cells [67]. Disruption of Stat1 can prevent IFNg-
induced b cell apoptosis mediated by autoimmune destruction in the non-obese diabetic
(NOD) mouse [68]. Furthermore, treatment of NOD mice with the JAK1/JAK2 inhibitor,
AZD1480, blocks MHC class I upregulation on b cells and can reverse diabetes in newly
diagnosed NOD mice [69]. IFNg is also responsible for upregulation of CXCL10, which is
overexpressed in islets from both individuals with T1D [70] and T2D [71], and is associated with
b cell apoptosis. Taken together, these results suggest that targeting of the IFNg–STAT1
pathway in pancreatic b cells may be a promising therapeutic avenue for management of both
T1D and T2D.

Immune [376_TD$IF]Cells
Inflammation is a key feature of obesity and diabetes [72]. During obesity, there is chronic low-
grade inflammation that is associated with increased immune cells in adipose and liver that
contribute to insulin resistance. Given the well-established role of JAK/STAT signaling in
immune cell activation, it is not surprising that JAK/STAT signaling also plays an important

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role in obesity-associated inflammation and metabolic dysfunction. To date, immune cell JAK/
STAT signaling has been investigated in macrophages, natural killer (NK) cells, and T cells.

In macrophages, JAK/STAT signaling is necessary for activation by many cytokines and growth
factors including IFNg, IL4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and
GH. The in vivo role of JAK2 in macrophages was studied using myeloid-specific Jak2 KO mice,
which had reduced inflammation in the liver and adipose tissue, as well as improved insulin
sensitivity during HFD feeding [73]. These findings are potentially explained by a reduction in
expression of proinflammatory chemokines. Interestingly, deletion of Ghr in myeloid cells
actually resulted in an increase in adipose tissue inflammation associated with a shift from
M2 macrophage polarization to M1 [74]. Thus, JAK2 may not be an essential mediator of GH
signaling in myeloid cells, and further research will be necessary to determine which signaling
pathway was affected by Jak2 deletion. Another interesting pathway that has been studied in
vivo is the role of the IL4–STAT6 pathway in the formation of alternatively activated macro-
phages during cold-induced thermogenesis. In response to cold, tissue macrophages are
converted to alternative M2-like macrophages that stimulate lipolysis in WAT and thermogenic
gene expression in BAT. This process was shown to be dependent on IL4–STAT6 signaling,
and enhancement of this pathway through administration of IL4 can increase energy expendi-
ture in mice [75,76].

During obesity, an expansion of a unique subpopulation of IL6 receptor-positive NK cells has

been shown in both humans and mice [77]. The pathogenic role of these NK cells was
demonstrated through NK cell-specific deletion of the genes encoding IL6 receptor or its
downstream effector STAT3, which protected mice from diet-induced obesity, insulin resis-
tance, and inflammation.

Lastly, there is evidence implicating T lymphocyte JAK/STAT signaling in the pathogenesis of

obesity. As previously discussed, global Stat4 KO mice have reduced inflammation and insulin
resistance. To determine if lymphocyte STAT4 contributes to this phenotype, investigators
performed adoptive transfer of CD8+[374_TD$IF] and CD4+ T cells from control and Stat KO mice [78]. Mice
receiving STAT4-deficient CD8+ T cells had reduced adipose tissue and islet inflammation after
HFD feeding and improved glucose tolerance.

Taken together, these studies demonstrate the impact of immune JAK/STAT signaling on
obesity-associated inflammation and glucose homeostasis. Given the large number of different
immune cells and JAK/STAT proteins involved in inflammatory signaling, this is a promising area
of research with potential to identify novel therapeutic strategies.

Concluding Remarks and Future Prospects of Using JAK or STAT

Modulators for Treating Metabolic Diseases
In this review we have discussed the role of JAK/STAT signaling in the regulation of metabolic
homeostasis under physiologic and pathologic conditions. The functions of JAK/STAT proteins
are highly context-dependent and modulate a multitude of metabolic processes including
adiposity, energy expenditure, glucose tolerance, insulin sensitivity, and inflammation. Owing to
the fact that JAK/STAT signaling can have both physiological and pathological roles depending
on the context, it is difficult to predict how JAK/STAT inhibition will affect individuals with obesity
and diabetes. With the use of tissue-specific KO mice, the essential roles of JAK2, STAT3, and
STAT5 have been demonstrated in the peripheral metabolic organs, including adipose, liver,
skeletal muscle, and pancreas (Figure 2). Thus, systemic JAK/STAT inhibition may result in
undesirable metabolic consequences due to effects in these organs. By contrast, inhibition of

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 TEM 1264 No. of Pages 11

IL6 Gh Gh

Liver Adipose
STAT3 JAK2 JAK2
IGF1
STAT5 STAT3 STAT5

Gluconeogenesis Steatosis Adiposity

Lipolysis

EPO GH Gh IL6

Islet Glucose Insulin Muscle

tolerance sensiƟvity STAT3
JAK2 STAT5 STAT3

? Growth and lipid InflammaƟon

β cell Insulin
mass secreƟon metabolism ?

InflammaƟon

JAK2 STAT3 STAT4

Mac NK T cell

Figure 2. Model of JAK/STAT Signaling in the Regulation of Whole-Body Metabolism. A simplified working model outlining the tissue-specific metabolic roles
of JAK/STAT proteins that have been investigated in vivo with conditional knockout mice. Normal JAK/STAT functions are depicted in the peripheral metabolic organs
including adipose, liver, muscle, pancreatic islets, macrophages (Mac), natural killer (NK) cells, and T cells. Effects on glucose tolerance, insulin sensitivity, and adiposity
are indicated as either a green arrow (promoting) or red bar (inhibiting). Question marks indicate areas of uncertainty.

these same proteins in immune cells appears to have beneficial effects, with reduced inflam-
mation and insulin resistance. There is also great potential in the other JAK/STAT proteins that
have yet to be characterized in vivo. For example, STAT1 activity is associated with insulin
resistance in muscle, apoptosis in islets, and immune cell activation. Thus, further investigation
into the in vivo metabolic function of additional proteins such as JAK1, JAK3, TYK2, STAT1,
STAT2, STAT4, and STAT6 can potentially lead to the identification of suitable therapeutic
targets.

In our discussion we focused primarily on cytoplasmic/nuclear STAT proteins; however, there is

a growing body of literature demonstrating that most STAT proteins are also found in mito-
chondria [79]. Mitochondrial STAT3 in particular has been closely linked to mitochondrial
function and cellular ATP levels [80]. The impact of mitochondrial STAT proteins on whole-
body metabolism and glucose homeostasis has yet to be investigated, highlighting this as an
important area for future research.

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 TEM 1264 No. of Pages 11

In this review we also discussed novel treatment avenues for diabetes, including adipose tissue Outstanding Questions
‘browning’ and the formation of pancreatic ‘b-like’ cells, crucial processes that are regulated by The tissue-specific roles of JAK2,
JAK/STAT signaling. In addition, with increasing use of JAK inhibitors for various diseases there STAT3, and STAT5 have been well-
studied in vivo, but what are the tis-
will be more opportunities to observe the clinical effects of targeting this pathway. Current sue-specific metabolic functions of the
pharmaceutical agents target multiple JAK proteins, but more specific inhibitors are being remaining JAK/STAT proteins includ-
developed and will likely be useful agents for testing in preclinical models of obesity and ing JAK1, JAK3, TYK2, STAT1,
STAT2, STAT4, and STAT6?
diabetes. In addition, as more ongoing clinical trial data become available we will collect
outcomes of metabolic effects of JAK/STAT inhibition in humans. These and other areas of
Owing to the limitations of currently
future study are highlighted in the Outstanding Questions. In summary, this review highlights the available technology, investigation into
crucial function of JAK/STAT signaling in the regulation of metabolic homeostasis, and that with the in vivo roles of JAK/STAT proteins
ongoing research the JAK/STAT pathway presents a novel array of potential therapeutic targets has largely relied on congenital KO
models. As technologies advance to
in the treatment of metabolic disease.
improve tissue- and age-dependent
manipulation of gene expression, will
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