Markers of Inflammation Are Heritable and Associated with Subcutaneous and Ectopic Skeletal Muscle Adiposity in African Ancestry Families

Although obesity is a major driver of type 2 diabetes (T2D), many obese individuals do not develop T2D. Indeed, fat around and within non-adipose tissue organs (i.e., ectopic fat) is emerging as a strong risk factor for diabetes. The potential differential contribution of ectopic fat depots throughout the body on T2D risk is unclear because studies have mainly focused on visceral and/or liver fat. No study, to our knowledge, has addressed the potential independent association of visceral, liver, and skeletal muscle adiposity with T2D. Such studies are particularly needed among African ancestry populations, as generalized obesity and other risk factors do not appear to explain the high T2D burden in this population segment. To address this knowledge gap, we measured total body fat by DXA, and visceral, liver, and calf skeletal muscle adiposity by computed tomography in 490 Afro-Caribbean men, aged 50-91 years (mean age=64 years, mean BMI=27.5 kg/m 2 ). The prevalence of T2D in this population was 22.3%. We employed multiple logistic regression using total body fat percent and ectopic fat depots as predictors (Table). We found that each 7.9 HU decrease in liver attenuation (indicative of greater liver adiposity) was associated with a 33% increased odds of T2D (p=0.011). Similarly, each 4.2 mg/cm 3 decrease in muscle attenuation (indicative of greater intra-muscular adiposity) was associated with a 31% increased odds of T2D (p=0.04). These associations were independent of total and visceral adiposity. Our results support the “ectopic fat syndrome” theory, as opposed to the “portal theory”, in the pathogenesis of diabetes among African ancestry men. Longitudinal studies are needed to clarify the exact role of specific ectopic fat depots in T2D, particularly in high-risk African ancestry populations.

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Wnt Pathway Inhibitor DKK1: A Potential Novel Biomarker for Adiposity

Journal of the Endocrine Society ◽

10.1210/js.2018-00325 ◽

2019 ◽

Vol 3 (2) ◽

pp. 488-495 ◽

Cited By ~ 5

Author(s):

Hira Ali ◽

Joseph M Zmuda ◽

Ryan K Cvejkus ◽

Erin E Kershaw ◽

Allison L Kuipers ◽

...

Keyword(s):

Skeletal Muscle ◽

Wnt Pathway ◽

African Ancestry ◽

Model Assessment ◽

Fasting Serum ◽

Muscle Area ◽

Muscle Density ◽

Muscle Adiposity ◽

Total Body

Abstract Emerging evidence indicates that ectopic skeletal muscle adiposity may be a risk factor for type 2 diabetes (T2D), especially in persons of African ancestry. In vitro studies suggest that a Wnt pathway inhibitor, Dickkopf-related protein 1 (DKK1), plays a role in adiposity regulation and could be a biomarker for adiposity in humans. The objective of this study was to test whether serum DKK1 levels relate to adiposity measures in a cohort from an African ancestry population at high risk for T2D. Fasting serum DKK1 was measured in a sample of 159 men of African ancestry aged ≥40 years (mean age ± SD, 63.5 ± 8.2 years; mean body mass index, 27.8 ± 4.5 kg/m2). Anthropometrics included total-body and trunk adiposity measured by dual-energy x-ray absorptiometry and lower-leg skeletal muscle density measured by CT [which reflects the intramuscular adiposity content (mg/cm3)]. Serum DKK1 was positively correlated with BMI (r = 0.20; P = 0.01), waist circumference (r = 0.15; P = 0.046), DXA total-body adiposity (r = 0.24; P = 0.003), and DXA trunk adiposity (r = 0.21; P = 0.009), independent of age and height. In addition, serum DKK1 was inversely correlated with skeletal muscle density (r = −0.25; P = 0.002), independent of age, BMI, and calf muscle area. No significant correlation was found between serum DKK1 and fasting serum glucose or insulin levels or insulin resistance estimated by homeostasis model assessment. These findings suggest that higher levels of serum DKK1 may be associated with greater overall, central, and ectopic skeletal muscle adiposity. Further studies are needed to unravel the potential role of DKK1 in the regulation of adiposity in humans.

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Hepatic and Skeletal Muscle Adiposity Are Associated with Diabetes Independent of Visceral Adiposity in Nonobese African-Caribbean Men

Metabolic Syndrome and Related Disorders ◽

10.1089/met.2019.0097 ◽

2020 ◽

Vol 18 (6) ◽

pp. 275-283

Author(s):

Iva Miljkovic ◽

Allison L. Kuipers ◽

Ryan K. Cvejkus ◽

J. Jeffrey Carr ◽

James G. Terry ◽

...

Keyword(s):

Skeletal Muscle ◽

Visceral Adiposity ◽

African Caribbean ◽

Muscle Adiposity

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Skeletal muscle adiposity is associated with serum lipid and lipoprotein levels in Afro-Caribbean men

Obesity ◽

10.1002/oby.20214 ◽

2013 ◽

Vol 21 (9) ◽

pp. 1900-1907 ◽

Cited By ~ 3

Author(s):

I. Miljkovic ◽

A.L. Kuipers ◽

L.H. Kuller ◽

Y. Sheu ◽

C.H. Bunker ◽

...

Keyword(s):

Skeletal Muscle ◽

Serum Lipid ◽

Muscle Adiposity

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Adipose tissue infiltration in skeletal muscle: age patterns and association with diabetes among men of African ancestry

American Journal of Clinical Nutrition ◽

10.1093/ajcn/87.6.1590 ◽

2008 ◽

Vol 87 (6) ◽

pp. 1590-1595 ◽

Cited By ~ 70

Author(s):

Iva Miljkovic-Gacic ◽

Christopher L Gordon ◽

Bret H Goodpaster ◽

Clareann H Bunker ◽

Alan L Patrick ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

African Ancestry ◽

Age Patterns

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Baseline Quantitative Computed Tomography Measures of Skeletal Muscle Adiposity and Lung Function Trajectory in the Severe Asthma Research Program

10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a1109 ◽

2021 ◽

Author(s):

M.C. Tattersall ◽

N. Tsuchiya ◽

D.G. Benson ◽

K.E. Lee ◽

C. Korcarz ◽

...

Keyword(s):

Computed Tomography ◽

Skeletal Muscle ◽

Lung Function ◽

Severe Asthma ◽

Research Program ◽

Quantitative Computed Tomography ◽

Muscle Adiposity

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Skeletal Muscle Mitochondrial Dysfunction Is Present in Patients with CKD before Initiation of Maintenance Hemodialysis

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.10320819 ◽

2020 ◽

Vol 15 (7) ◽

pp. 926-936 ◽

Cited By ~ 4

Author(s):

Jorge L. Gamboa ◽

Baback Roshanravan ◽

Theodore Towse ◽

Chad A. Keller ◽

Aaron M. Falck ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Mitochondrial Dysfunction ◽

Physical Performance ◽

Mitochondrial Function ◽

Maintenance Hemodialysis ◽

Intermuscular Adipose Tissue ◽

Markers Of Inflammation ◽

And Oxidative Stress

Background and objectivesPatients with CKD suffer from frailty and sarcopenia, which is associated with higher morbidity and mortality. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. In this study, we tested the hypothesis that mitochondrial dysfunction is associated with the severity of CKD. We also evaluated the interaction between mitochondrial function and coexisting comorbidities, such as impaired physical performance, intermuscular adipose tissue infiltration, inflammation, and oxidative stress.Design, setting, participants, & measurements Sixty-three participants were studied, including controls (n=21), patients with CKD not on maintenance hemodialysis (CKD 3–5; n=20), and patients on maintenance hemodialysis (n=22). We evaluated in vivo knee extensors mitochondrial function using 31P magnetic resonance spectroscopy to obtain the phosphocreatine recovery time constant, a measure of mitochondrial function. We measured physical performance using the 6-minute walk test, intermuscular adipose tissue infiltration with magnetic resonance imaging, and markers of inflammation and oxidative stress in plasma. In skeletal muscle biopsies from a select number of patients on maintenance hemodialysis, we also measured markers of mitochondrial dynamics (fusion and fission).ResultsWe found a prolonged phosphocreatine recovery constant in patients on maintenance hemodialysis (53.3 [43.4–70.1] seconds, median [interquartile range]) and patients with CKD not on maintenance hemodialysis (41.5 [35.4–49.1] seconds) compared with controls (38.9 [32.5–46.0] seconds; P=0.001 among groups). Mitochondrial dysfunction was associated with poor physical performance (r=0.62; P=0.001), greater intermuscular adipose tissue (r=0.44; P=0.001), and increased markers of inflammation and oxidative stress (r=0.60; P=0.001). We found mitochondrial fragmentation and increased content of dynamin-related protein 1, a marker of mitochondrial fission, in skeletal muscles from patients on maintenance hemodialysis (0.86 [0.48–1.35] arbitrary units (A.U.), median [interquartile range]) compared with controls (0.60 [0.24–0.75] A.U.).ConclusionsMitochondrial dysfunction is due to multifactorial etiologies and presents prior to the initiation of maintenance hemodialysis, including in patients with CKD stages 3–5.

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Wnt Pathway Inhibitor DKK1—A Potential Novel Biomarker for Ectopic Skeletal Muscle Adiposity

Diabetes ◽

10.2337/db18-2100-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 2100-P

Author(s):

HIRA ALI ◽

JOSEPH M. ZMUDA ◽

RYAN CVEJKUS ◽

ERIN E. KERSHAW ◽

ALLISON L. KUIPERS ◽

...

Keyword(s):

Skeletal Muscle ◽

Wnt Pathway ◽

Muscle Adiposity

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PSII-18 The effects of fish oil supplementation on markers of inflammation and skeletal muscle and adipose growth in pigs

Journal of Animal Science ◽

10.1093/jas/skab235.578 ◽

2021 ◽

Vol 99 (Supplement_3) ◽

pp. 314-315

Author(s):

Lillian L Okamoto ◽

Caleb C Reichhardt ◽

Sierra Lopez ◽

Anthony F Alberto ◽

Reganne K Briggs ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Fish Oil ◽

Muscle Growth ◽

Basal Diet ◽

Omega 3 Fatty Acids ◽

Omega 3 ◽

Lps Challenge ◽

Markers Of Inflammation ◽

Fish Oil Supplementation

Abstract Omega-3 fatty acids have immunomodulatory and anti-inflammatory effects. The objective of this project was to determine the effects of fish oil, a source of omega-3 fatty acids, on genes involved in inflammation and growth of skeletal muscle tissue after an LPS challenge. Male Landrace-New Hampshire weaned piglets (BW 8.21±0.83 kg) were used in a randomized complete block design and assigned to two treatments: 1) basal diet (n=7) and 2) basal diet plus 3% fish oil added (n = 7). Treatments were fed for 35 d. On d 34, an LPS challenge was performed and 24 h later, piglets were euthanized and skeletal muscle samples were collected from the longissimus lumborum and biceps femoris. Total mRNA was isolated and markers of inflammation [cyclophilin (Cyclo), nuclear factor kappa beta subunit-1 (NF-kB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6)], skeletal muscle growth [paired box transcription factor-7 (Pax7), myogenic factor-5 (Myf5), myoblast determination factor-1 (MyoD), myogenin (MyoG)] and adipose growth (peroxisome proliferator activated receptor (PPARy), leptin, and adiponectin) were analyzed. Cyclophilin abundance was increased (P = 0.03) in fish-oil piglets compared to control piglets. Other markers of inflammation (TNF-α, IL-6, NF-kB) were not affected (P > 0.05) by fish-oil supplementation. Abundance of Myf5 was lower (P = 0.03) in fish oil piglets than control piglets. Other myogenic regulatory factors (Pax7, MyoD, MyoG) were not (P > 0.05) altered by treatment. Abundance of PPARy, leptin or adiponectin was not affected (P > 0.05) by fish-oil supplementation. Muscle location influenced (P < 0.01) abundance of leptin and adiponectin, with abundance being higher in the biceps femoris than in the longissimus lumborum. No other genes analyzed were impacted by muscle location (P > 0.05). Our findings suggest that supplementation of omega-3 fatty acids via fish-oil may affect the inflammatory response and skeletal muscle growth. Further research is needed to evaluate the impact of these results on animal production.

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Abstract P363: Ectopic Adiposity is Associated With Abdominal Aorto-Illiac but Not Coronary Artery Calcification Independent of Total Body Adiposity in African Ancestry Men

Circulation ◽

10.1161/circ.135.suppl_1.p363 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Allison L Kuipers ◽

Joseph M Zmuda ◽

J Jeffrey Carr ◽

James G Terry ◽

Sangeeta Nair ◽

...

Keyword(s):

Cardiovascular Disease ◽

Skeletal Muscle ◽

Coronary Artery ◽

Vascular Disease ◽

Vascular Calcification ◽

Body Fat ◽

Coronary Artery Calcification ◽

African Ancestry ◽

Total Body Fat ◽

Total Body

Objective: While ectopic adiposity is considered a risk factor for many chronic diseases, including cardiovascular disease, the extent to which this association is independent of total adiposity is yet to be established. Vascular calcification, which is associated with greater adiposity, is a subclinical marker of cardiovascular disease that may have varying etiology and clinical implications in different vascular beds. Therefore, our objective was to assess the potential independent associations of total, regional and ectopic adiposity measures with abdominal aorto-iliac calcification (AAC) and coronary artery calcification (CAC). Methods: Detailed health history, clinical exam, dual x-ray absorptiometry and computed tomography (CT) scans were obtained in 798 African ancestry men aged ≥40 years (mean(SD): 62.0(8.6)years) recruited without regard to health status from the Tobago Heart Health Study. Vascular calcification was measured by CT in the abdomen (AAC) and chest (CAC). Calcification was scored using the Agatston method and a score ≥10 was considered to be a prevalent calcification. Severity of calcification was modeled using continuous Agatston score in those with any calcification. Multivariable logistic and linear regression models were used to assess the cross-sectional association of adiposity measures with vascular calcification prevalence and severity. All models were adjusted for age, hypertension, diabetes, dyslipidemia, smoking, alcohol intake and sedentary lifestyle. In addition, models of ectopic adiposity (abdominal visceral adipose tissue, liver attenuation and calf skeletal muscle fat) were adjusted for total body fat. Results: AAC was present in 63% and CAC was present in 29% of men. After adjustment for traditional cardiovascular risk factors, 1SD greater total, trunk, or abdominal subcutaneous adiposity was associated with 1.3-1.5-fold increased odds of AAC (all p<0.05). After additional adjustment for total body fat, 1SD lower liver attenuation (indicative of greater liver adiposity) or 1SD greater skeletal muscle fat were each associated with a 1.2-1.3-fold increased odds of AAC. In fully adjusted models, only greater BMI or waist circumference was associated with increased odds of CAC (OR 1.2, p<0.05 for both). In fully adjusted linear models of calcification severity, no significant association was observed between any adiposity measure and AAC or CAC. Conclusions: Independent of total adiposity, measures of ectopic adiposity were associated with greater AAC, but not CAC, prevalence in African ancestry men. These results highlight potential differences in the adiposity-vascular disease relationship that may vary by ectopic fat depot and vascular bed location. Future vascular disease research should explore potential underlying biologic mechanisms for these findings.

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