HSP47 levels determine the degree of body adiposity

概要

Title

HSP47 levels determine the degree of body
adiposity

Author(s)

Shin, Jihoon; Toyoda, Shinichiro; Okuno, Yosuke
et al.

Citation

Nature Communications. 2023, 14, p. 7319

Version Type VoR
URL
rights

https://hdl.handle.net/11094/93378
This article is licensed under a Creative
Commons Attribution 4.0 International License.

Note

Osaka University Knowledge Archive : OUKA
https://ir.library.osaka-u.ac.jp/
Osaka University

Article

https://doi.org/10.1038/s41467-023-43080-x

HSP47 levels determine the degree of body
adiposity
Received: 9 March 2023
Accepted: 31 October 2023

Jihoon Shin 1,2,3 , Shinichiro Toyoda1, Yosuke Okuno1, Reiko Hayashi1,
Shigeki Nishitani1, Toshiharu Onodera1,4, Haruyo Sakamoto1, Shinya Ito5,
Sachiko Kobayashi 1, Hirofumi Nagao 1, Shunbun Kita 1,6, Michio Otsuki1,7,
Atsunori Fukuhara 1,6, Kazuhiro Nagata8,9 & Iichiro Shimomura1

Adiposity varies among individuals with the influence of diverse physiological,
pathological, environmental, hormonal, and genetic factors, but a unified
molecular basis remains elusive. Here, we identify HSP47, a collagen-specific
chaperone, as a key determinant of body adiposity. HSP47 expression is
abundant in adipose tissue; increased with feeding, overeating, and obesity;
decreased with fasting, exercise, calorie restriction, bariatric surgery, and
cachexia; and correlated with fat mass, BMI, waist, and hip circumferences.
Insulin and glucocorticoids, respectively, up- and down-regulate HSP47
expression. In humans, the increase of HSP47 gene expression by its intron or
synonymous variants is associated with higher body adiposity traits. In mice,
the adipose-specific knockout or pharmacological inhibition of HSP47 leads to
lower body adiposity compared to the control. Mechanistically, HSP47 promotes collagen dynamics in the folding, secretion, and interaction with
integrin, which activates FAK signaling and preserves PPARγ protein from
proteasomal degradation, partly related to MDM2. The study highlights the
significance of HSP47 in determining the amount of body fat individually and
under various circumstances.

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Adipose tissue, composed of adipocytes, is a specialized organ to store
energy as fat, thus commonly referred to as fat tissue1. It is distributed
throughout the body, including subcutaneous fat beneath the skin,
visceral fat around internal organs, and brown fat in the back, neck,
and shoulder area2. Fat tissue can dynamically change its size and mass
in response to nutritional and hormonal states. During eating or
overeating conditions, increased blood insulin levels stimulate glucose
uptake and lipid accumulation in fat cells, promoting the expansion of
fat tissue3. Conversely, fasting or starving conditions induce glucocorticoid hormone, which triggers the lipolysis of stored fat, leading to

a reduction in fat tissue4. The peroxisome proliferator-activated
receptor-γ (PPARγ) is a master regulator of fat cells5. Defects in
PPARγ result in the loss of fat tissue6–9, while its activation by agonizts,
such as pioglitazone, promotes lipid storage and the expansion of fat
tissue10,11. The unique properties of fat tissue and its regulation by
various nutritional, hormonal, and molecular factors have been well
established, yet the intricate connections between these elements is
not fully understood.
Adiposity, referring to the amount or percentage of body fat,
varies greatly between individuals, ranging from as low as 5% in very

1

Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. 2Department of Diabetes Care Medicine, Graduate
School of Medicine, Osaka University, Suita, Osaka, Japan. 3Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and
Harvard Medical School, Boston, MA, USA. 4Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical
Center, Dallas, USA. 5Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan. 6Department of Adipose Management, Graduate School of Medicine,
Osaka University, Suita, Osaka, Japan. 7Department of Endocrinology, Graduate School of Medical Science, Tokyo Women’s Medical University, Tokyo, Japan.
8
Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, Japan. 9JT Biohistory Research Hall, Osaka, Japan.
e-mail: shinjihoon0209@gmail.com

Nature Communications | (2023)14:7319

1

Article
thin/lean people to over 40% in the cases of morbid obesity12. Additionally, each person exhibits a unique susceptibility to gain body fat
under regular eating or overeating conditions13. These individual variations are influenced by a combination of physiological, environmental, pathological, and genetic factors. Physiologically, eating habits
and patterns, which affect food calorie intake, fasting duration, and
hormone levels, have a significant impact on body adiposity14,15.
Environmentally, engaging in high physical activity or exercise can also
contribute to lower body adiposity14,15. Pathologically, obesity is characterized by high levels of body fat tissue15, while cachexia, a wasting
disorder, leads to a significant loss of fat tissue16. Bariatric surgery has
been shown effective results in reducing body adiposity in patients
with obesity17. Genetic factors, such as single nucleotide polymorphisms (SNPs), also play a role in determining body adiposity traits, such
as fat mass, BMI, waist circumference, and hip circumferences18.
Despite the comprehensive contribution of physiological, pathological, environmental, and genetic backgrounds to body adiposity, a
unified molecular basis for its regulation remains elusive.
In this study, through a series of in silico, in vivo, and in vitro
experiments, we identify HSP47, a collagen-specific molecular
chaperone19,20, as a significant determinant of body adiposity. Our
transcriptomic and genetic analyses indicate that HSP47 is prominently expressed in adipose tissue and adipocytes, with its levels
tightly linked to the degree of body adiposity in humans. Adiposespecific and pharmacological ablation models in mice provide compelling evidence of the causal impact of HSP47 on body fat deposition.
Biochemical assays reveal that HSP47-meidated enhancement of collagen protein dynamics, such as its folding, secretion, and binding in
the extracellular matrix, induce focal adhesion signaling, stabilize
PPARγ protein, and ultimately lead to the expansion of fat tissue. This
research not only deepens our understanding of the individual and
contextual factors that determine body adiposity but also provides a
robust scientific rationale for these mechanisms.

Results
Collagen matrix, focal adhesion, and PPARγ characterize
fat tissue
Each organ/tissue has its unique characteristics, which are defined by
their specific gene expression patterns21. To understand the characteristics of fat tissue in transcription levels, we compared the gene
expression patterns of adipose tissue with those of other 52 different
organs and tissues. We scored the adipose enrichment of each transcript and plotted it against the gene expression level. As expected,
ADIPOQ (Adiponectin), LEP (Leptin), and FABP4 (aP2) genes were
found to be highly enriched and expressed in adipose tissue (Fig. 1a).
We performed gene ontology (GO) analysis on the top 500 genes and
found that components of the collagen-containing ECM and focal
adhesion were enriched in fat tissue (Fig. 1b). Pathway analysis further
revealed that these genes are involved in the PPAR signaling pathway,
ECM-receptor interaction, and focal adhesion (Fig. 1c). Focal adhesion
is subcellular structures composed of multiple proteins, including
Integrins and focal adhesion kinase (FAK), that serves as a link between
the extracellular environment and intracellular compartments22,23.
Therefore, the interactions between extracellular collagen matrix,
subcellular focal adhesion, and intracellular PPARγ may play a crucial
role in shaping the characteristics of adipose tissue.

https://doi.org/10.1038/s41467-023-43080-x

tissue, (3) induced by overeating (8 weeks of high-fat diet) in human
subcutaneous adipose tissue, (4) upregulated by obesity in human
adipocytes, and (5) associated with various adiposity traits in human
genome-wide association study (GWAS), such as waist circumferences,
hip circumferences, waist/hip ratio, obesity, and BMI. Through this
comparative analysis, we identified HSP47, a collagen-specific chaperone encoded by SERPINH1 gene19,20, as a potential determinant of
body adiposity.
Detailed expression profiles revealed that HSP47 gene and protein
are highly expressed in adipose tissues and adipocytes compared with
other tissues, organs, and cells in humans (Fig. 1e, f). Similar expression
patterns were observed in mice (Supplementary Fig. 1a–c). The gene
expression of HSP47 increased in human adipose tissues with feeding
(Fig. 1g) and overeating (Fig. 1h). Individuals with obesity exhibited
higher gene expression of HSP47 in adipocytes (Fig. 1i). There were no
significant sexual differences of HSP47 expression in subcutaneous
and visceral adipose tissues (Supplementary Fig. 2a); both male and
female subjects displayed equivalent induction of HSP47 in obesity
(Supplementary Fig. 2b). We also analyzed adipose tissues from young
adult (22- to 36-year-old) monozygotic twin-pairs with discordant BMI
(inter-pair difference ΔBMI > 3 kg/m2), which showed significant differences in various body adiposity traits such as body weight, fat mass,
and volume26. The gene expression of HSP47 was significantly higher in
the adipose tissue of high-adiposity monozygotic twin pairs compared
to that of low-adiposity twin pairs (Fig. 1j), indicating that HSP47 gene
expression associates with body adiposity independent of genetic
backgrounds. In contrast, HSP47 gene expression was significantly
lower in adipose tissues under low-adiposity conditions, such as
exercise training (Fig. ...

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