Biotin-dependent functions in adiposity: a study of monozygotic twin pairs

ABSTRACT BACKGROUND: Biotin acts as a coenzyme for carboxylases regulating lipid and amino-acid metabolism. We investigated alterations of the biotin-dependent functions in obesity and the

downstream effects of biotin restriction in adipocytes _in vitro_. SUBJECTS: Twenty-four monozygotic twin pairs discordant for body mass index (BMI). Mean within-pair difference (heavy-lean

co-twin, Δ) of BMI was 6.0 kg m–2 (range 3.1–15.2 kg m–2). METHODS: Adipose tissue (AT) DNA methylation, gene expression of AT and adipocytes, and leukocytes (real-time quantitative PCR),

serum biotin, C-reactive protein (CRP) and triglycerides were measured in the twins. Human adipocytes were cultured in low and control biotin concentrations and analyzed for lipid droplet

content, mitochondrial morphology and mitochondrial respiration. RESULTS: The gene expression levels of carboxylases, _PCCB_ and _MCCC1_, were upregulated in the heavier co-twins’

leukocytes. Δ_PCCB_ (_r_=0.91, _P_=0.0046) and Δ_MCCC_1 (_r_=0.79, _P_=0.036) correlated with ΔCRP within-pairs. Serum biotin levels were lower in the heavier (274 ng l–1) than in the lean

co-twins (390 ng l–1, _P_=0.034). ΔBiotin correlated negatively with Δtriglycerides (_r_=–0.56, _P_=0.045) within-pairs. In AT, _HLCS_ and _ACACB_ were hypermethylated and biotin cycle genes

_HLCS_ and _BTD_ were downregulated (_P_<0.05). Biotin-dependent carboxylases were downregulated (_ACACA_, _ACACB_, _PCCB_, _MCCC2_ and _PC_; _P_<0.05) in both AT and adipocytes of

the heavier co-twins. Adipocytes cultured in low biotin had decreased lipid accumulation, altered mitochondrial morphology and deficient mitochondrial respiration. CONCLUSIONS:

Biotin-dependent functions are modified by adiposity independent of genetic effects, and correlate with inflammation and hypertriglyceridemia. Biotin restriction decreases lipid accumulation

and respiration, and alters mitochondrial morphology in adipocytes. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article *

Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn

about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS _F13A1_ TRANSGLUTAMINASE EXPRESSION IN HUMAN ADIPOSE TISSUE INCREASES IN

ACQUIRED EXCESS WEIGHT AND ASSOCIATES WITH INFLAMMATORY STATUS OF ADIPOCYTES Article 21 November 2020 TWIN PAIR ANALYSIS UNCOVERS LINKS BETWEEN DNA METHYLATION, MITOCHONDRIAL DNA QUANTITY

AND OBESITY Article Open access 12 May 2025 MORBIDLY OBESE SUBJECTS SHOW INCREASED SERUM SULFIDE IN PROPORTION TO FAT MASS Article 10 October 2020 REFERENCES * Pietiläinen KH, Naukkarinen J,

Rissanen A, Saharinen J, Ellonen P, Keränen H _et al_. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. _PLOS Med_ 2008; 5: e51.

Article  Google Scholar  * Pietiläinen KH, Rog T, Seppänen-Laakso Virtue S, Gopalacharyulu P, Tang J _et al_. Association of lipidome remodeling in the adipocyte membrane with acquired

obesity in humans. _PLOS Biol_ 2011; 9: e1000623. Article  Google Scholar  * Nunnari J, Suomalainen A . Mitochondria: in sickness and in health. _Cell_ 2012; 148: 1145–1159. Article  CAS 

Google Scholar  * McGarry JD . Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. _Diabetes_ 2002; 51: 7–18. Article  CAS  Google Scholar  *

Muoio DM . Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock. _Cell_ 2014; 159: 1253–1262. Article  CAS  Google Scholar  * Malandrion MI, Fucho R, Weber M,

Calderon-Dominguez M, Mir JF, Valcarcel L _et al_. Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation. _Am J Physiol

Endocrinol Metab._ 2015; 308: 756–769. Article  Google Scholar  * Hymes J, Fleischhauer K, Wolf B . Biotinylation of histones by human serum biotinidase: assessment of biotinyl-transferase

activity in sera from normal individuals and children with biotinidase deficiency. _Biochem Mol Med_ 1995; 56: 76–83. Article  CAS  Google Scholar  * Pestinger V, Wijeratne SS,

Rodriguez-Melendez R, Zempleni J . Novel histone biotinylation marks are enriched in repeat regions and participate in repression of transcriptionally competent genes. _J Nutr Biochem_ 2011;

22: 328–333. Article  CAS  Google Scholar  * Maebashi M, Makino Y, Ohinata K, Kimura S, Takao S . Therapeutic evaluation of the effect of biotin on hyperglycemia in patients with

non-insulin diabetes mellitus. _J Clin Biochem Nutr_ 1993; 14: 211–218. Article  Google Scholar  * Marshall MW, Kliman PG, Washington VA, Mackin JF, Weinland BT . Effects of biotin on lipids

and other constituents of plasma of healthy men and women. _Artery_ 1980; 7: 330–351. CAS  PubMed  Google Scholar  * Larrieta E, Velasco F, Vital P, López-Aceves T, Lazo-de-la-Vega-Monroy

ML, Rojas A _et al_. Pharmacological concentrations of biotin reduce serum triglycerides and the expression of lipogenic genes. _Eur J Pharmacol_ 2010; 644: 263–268. Article  CAS  Google

Scholar  * Báez-Saldaña A, Zendejas-Ruiz I, Revilla-Monsalve C, Islas-Andrade S, Cárdenas A, Rojas-Ochoa A _et al_. Effects of biotin on pyruvate carboxylase, acetyl-CoA carboxylase,

propionyl-CoA carboxylase, and markers for glucose and lipid homeostasis in type 2 diabetic patients and nondiabetic subjects. _Am J Clin Nutr_ 2004; 79: 238–243. Article  Google Scholar  *

Ollikainen M, Ismail K, Gervin K, Kyllönen A, Hakkarainen A, Lundbom J _et al_. Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in

monozygotic twins discordant for obesity and liver fat. _Clin Epigenetics_ 2015; 7: 39–51. Article  Google Scholar  * Heinonen S, Buzkova J, Muniandy M, Kaksonen R, Ollikainen M, Ismail K

_et al_. Impaire mitochondrial biogenesis in adipose tissue in acquired obesity. _Diabetes_ 2015; 64: 3135–3145. Article  CAS  Google Scholar  * Kaprio J, Pulkkinen L, Rose RJ . Genetic and

environmental factors in health-related behaviors: studies on Finnish twins and twin families. _Twin Res_ 2002; 5: 366–371. Article  Google Scholar  * Teschendorff AE, Marabita F, Lechner M,

Bartlett T, Tegner J, Gomez-Cabrero D, Beck S . A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data.

_Bioinformatics_ 2013; 29: 189–196. Article  CAS  Google Scholar  * Leek JT, Storey JD . Capturing heterogeneity in gene expression studies by surrogate variable analysis. _PLOS Genet_ 2007;

3: 1724–1735. Article  CAS  Google Scholar  * Wu Z, Irizarry RA, Gentleman R, Murillo FM, Spencer F . A model based background adjustment for oligonucleotide expression arrays. _J Am Stat

Association_ 2004; 99: 909–917. Article  Google Scholar  * Van Harmelen V, Skurk T, Hauner H . Primary culture and differentiation of human adipocyte precursor cells. _Methods Mol Med_ 2005;

107: 125–135. CAS  PubMed  Google Scholar  * Skurk T, Hauner H . Primary culture of human adipocyte precursor cells: expansion and differentiation. _Methods Mol Biol_ 2012; 806: 215–226.

Article  CAS  Google Scholar  * Smyth GK, Michaud J, Scott HS . Use of within-array replicate spots for assessing differential expressions in microarray experiments. _Bioinformatics_ 2005;

21: 2067–2075. Article  CAS  Google Scholar  * Naukkarinen J, Heinonen S, Hakkarainen A, Lundbom J, Vuolteenaho K, Saarinen L _et al_. Characterising metabolically healthy obesity in

weight-discordant monozygotic twins. _Diabetologia_ 2014; 57: 167–176. Article  CAS  Google Scholar  * Heinonen S, Saarinen L, Naukkarinen J, Rodríguez A, Frühbeck G, Hakkarainen A _et al_.

Adipocyte morphology and implications for metabolic derangements in acquired obesity. _Int J Obes_ 2014; 38: 1423–1431. Article  CAS  Google Scholar  * Abu-Elheiga L, Wu H, Gu Z, Bressler R,

Wakil SJ . Acetyl-CoA carboxylase 2-/- mutant mice are protected against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions. _J Biol Chem_ 2012; 287:

12578–12588. Article  CAS  Google Scholar  * Olson DP, Pulinilkunnil T, Cline GW, Shulman GI, Lowell BB . Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake.

_Proc Natl Acad Sci USA_ 2010; 107: 7598–7603. Article  CAS  Google Scholar  * Kuri-Harcuch W, Wise LS, Green H . Interruption of the adipose conversion of 3T3 cells by biotin deficiency:

differentiation without triglyceride accumulation. _Cell_ 1978; 14: 53–59. Article  CAS  Google Scholar  * Gomes LC, Di Benedetto G, Scorrano L . During autophagy mitochondria elongate, are

spared from degradation and sustain cell viability. _Nat Cell Biol_ 2011; 13: 589–598. Article  CAS  Google Scholar  * Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J . Tubular

network formation protects mitochondria from autophagosomal degradation during nutrient starvation. _Proc Natl Acad Sci USA_ 2011; 108: 10190–10195. Article  CAS  Google Scholar  * Rambold

AS, Cohen S, Lippincott-Schwartz J . Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. _Dev Cell_ 2015; 32:

678–692. Article  CAS  Google Scholar  * Virtue S, Vidal-Puig A . Adipose tissue expandability, lipotoxicity and the metabolic syndrome – an allostatic perspective. _Biochim Biophys Acta_

2010; 1801: 338–349. Article  CAS  Google Scholar  * Abu-Elheiga L, Oh W, Kordari P, Wakil SJ . Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by

high-fat/high-carbohydrate diets. _Proc Natl Acad Sci USA_ 2003; 100: 10207–10212. Article  CAS  Google Scholar  * Tong L . Structure and function of biotin-dependent carboxylases. _Cell Mol

Life Sci_ 2013; 70: 863–891. Article  CAS  Google Scholar  * Pacheco-Alvarez D, Solórzano-Vargas RS, Del Río AL . Biotin in metabolism and its relationship to human disease. _Arch Med Res_

2002; 33: 439–447. Article  CAS  Google Scholar  * Pérez-Monjaras A, Cervantes-Roldán R, Meneses-Morales I, Gravel RA, Reyes-Carmona S, Solórzano-Vargas S _et al_. Impaired biotinidase

activity disrupts holocarboxylase synthetase expression in late onset multiple carboxylase deficiency. _J Biol Chem_ 2008; 283: 34150–34158. Article  Google Scholar  Download references

ACKNOWLEDGEMENTS We want to thank all the volunteers for their valuable contribution, staff members of the Obesity Research Unit, especially Saila Saarinen, Mia Urjansson, Katja Sohlo and

Miia Juntunen and Anna-Maija Honkala for technical assistance, Mervi Lindman from the Electron microscopy unit at the Institute of Biotechnology and Jussi Kenkkilä from the Biomedicum

Imaging Unit for technical expertise and Uwe Richter for scientific advise. This study was supported by Helsinki University Hospital Research Funds and grants from the Novo Nordisk

Foundation (KP), Diabetes Research Foundation (KP, SH), Jalmari and Rauha Ahokas Foundation (KP, LB), Orion Pharmos Foundation (SH), Emil Aaltonen Foundation (SH), Finnish Medical Foundation

(SH), Finnish Foundation for Cardiovascular Research (KP), Finnish Funding Agency for Innovation (SM), Sigrid Juselius Foundation (MO), University of Helsinki Funds 490139 (MO), and Academy

of Finland (265240, 263278 (JK), 251316 (MO), EPITRAIN - FP7-PEOPLE-2012-ITN, grant agreement 316758 (JK, MO) and 266286 and 272376 (KP). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland E Järvinen, M Muniandy, S Heinonen, M Tummers, A Rissanen & K H Pietiläinen

* Department of Public Health, University of Helsinki, Helsinki, Finland K Ismail, L H Bogl, J Kaprio & M Ollikainen * BioMediTech, University of Tampere, Tampere, Finland S Miettinen *

Science Center, Tampere University Hospital, Tampere, Finland S Miettinen * FIMM, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland J Kaprio & K H Pietiläinen

* Department of Health, National Institute for Health and Welfare, Helsinki, Finland J Kaprio * Department of Psychiatry, Helsinki University Central Hospital and University of Helsinki,

Helsinki, Finland A Rissanen * Abdominal Center, Endocrinology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland K H Pietiläinen Authors * E Järvinen View

author publications You can also search for this author inPubMed Google Scholar * K Ismail View author publications You can also search for this author inPubMed Google Scholar * M Muniandy

View author publications You can also search for this author inPubMed Google Scholar * L H Bogl View author publications You can also search for this author inPubMed Google Scholar * S

Heinonen View author publications You can also search for this author inPubMed Google Scholar * M Tummers View author publications You can also search for this author inPubMed Google Scholar

* S Miettinen View author publications You can also search for this author inPubMed Google Scholar * J Kaprio View author publications You can also search for this author inPubMed Google

Scholar * A Rissanen View author publications You can also search for this author inPubMed Google Scholar * M Ollikainen View author publications You can also search for this author inPubMed

 Google Scholar * K H Pietiläinen View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to E Järvinen. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies this paper on International Journal of Obesity website

SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 (PPT 178 KB) SUPPLEMENTARY FIGURE 2 (PDF 11 KB) SUPPLEMENTARY TABLE 1 (XLSX 12 KB) SUPPLEMENTARY TABLE 2 (XLSX 24 KB) SUPPLEMENTARY

INFORMATION (DOCX 30 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Järvinen, E., Ismail, K., Muniandy, M. _et al._ Biotin-dependent functions in

adiposity: a study of monozygotic twin pairs. _Int J Obes_ 40, 788–795 (2016). https://doi.org/10.1038/ijo.2015.237 Download citation * Received: 17 June 2015 * Revised: 16 October 2015 *

Accepted: 06 November 2015 * Published: 25 November 2015 * Issue Date: May 2016 * DOI: https://doi.org/10.1038/ijo.2015.237 SHARE THIS ARTICLE Anyone you share the following link with will

be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative