Obesity and the diseases associated with it are among the biggest healthcare problems in developed countries. The word obesity means, simply, the accumulation of too much fat tissue in the body, but this ignores growing evidence that fat tissue is highly complex. Fat tissue is important for “mopping up” and storing excess calories safely, but also sends messages to the brain and other organs to report how full the body’s energy stores are. Understanding how fat tissues perform these roles will aid the development of strategies to treat or prevent obesity.

A hormone called leptin acts as a signal of the status of the body’s fat stores. High levels of leptin in the blood tell the brain that the body has plenty of fat stored. On the other hand, if the levels of leptin in the blood become very low it tells the brain to prioritize finding food and shut down any nonessential processes. This helps to prevent the body from starving. It is not clear how the production of leptin is controlled, in part because fat tissues in different parts of the body behave very differently.

Individuals who have a particular rare genetic mutation accumulate large amounts of fat tissue in their upper bodies and gradually lose fat tissue in their arms and legs. Despite accumulating a lot of fat tissue in the upper body, these individuals have extremely low levels of leptin in their blood. To investigate this genetic condition, Rocha et al. studied two children with the mutation and their healthy parents.

The experiments show that this mutation alters a protein called mitofusin 2, which is found in cell compartments called mitochondria. Mitofusin 2 helps the mitochondria to bind to each other and to other parts of the cell, which is important for the mitochondria to generate the energy needed for vital cell processes. The mitochondria in the fat cells of the children are less closely linked to each other and have an unusual appearance compared to the mitochondria in the parents’ fat cells. Further experiments showed that some genes, including the one that produces leptin, are less active in the children compared to their parents – while other genes that are involved in starvation or stress responses are more active.

This work suggests that mitochondria play an important role in regulating the production of leptin. Furthermore, it suggests that leptin or drugs that switch off stress-related genes may have the potential to be used to treat individuals with this particular mutation.

Adipose tissue is critical for metabolic homeostasis, and either global excess (obesity) or pathologic deficiency (lipodystrophy) lead to metabolic disease. Anatomically distinct adipose depots vary in embryological origins, gene expression profiles and patterns of hormonal regulation (Tchkonia et al., 2013), but many questions about the determinants of adipose depot differences, and their importance for metabolic regulation, remain unanswered. In studies of human metabolic disease, attention focussed for many years on visceral white adipose tissue, and on femorogluteal subcutaneous white adipose tissue, however interest has recently increased sharply in upper body subcutaneous adipose tissue, especially in interscapular and supraclavicular regions, where both obligate and facultative thermogenic adipocytes have been shown to exist under some circumstances (Betz and Enerbäck, 2015).

Since the mid 19th century a devastating but rare disease characterised by a selective, massive and sometimes life-threatening increase in upper body adipose tissue has been known (Brodie, 1846; Herbst, 2012; Madelung, 1888). This disease is called either multiple symmetrical lipomatosis (MSL) or Madelung’s disease. Although the degree of adipose overgrowth seen may be spectacular, it varies in distribution (Herbst, 2012) and the underlying pathogenesis, which is currently poorly understood, is likely to be heterogeneous. Previous studies have suggested hyperplasia of adipocytes which manifest impaired catecholamine-induced lipolysis (Enzi et al., 1977), and later structural studies of pathologically increased adipose tissue have suggested that it is composed of adipocytes with some morphological and metabolic features of dysfunctional brown adipocytes (Enzi et al., 2015). However MSL is not precisely defined, and phenotypic heterogeneity is apparent. People with MSL frequently exhibit variable additional features including peripheral neuropathy, autonomic neuropathy, non-alcoholic fatty liver disease and/or alcoholic liver disease, dyslipidaemia, and type 2 diabetes (Herbst, 2012). In some patients upper body adipose overgrowth contrasts with concomitant lipodystrophy in the femorogluteal region (Herbst, 2012). Physiological studies have described elevated resting energy expenditure, altered lipolytic rates and perturbed adipokine levels, however these findings have tended to vary, consistent with pathogenic heterogeneity (Herbst, 2012).

Sporadic MSL has been strongly linked to chronic alcohol excess (Enzi et al., 2015), and in rare cases is seen in the mitochondrial myoclonus epilepsy and ragged red fibers (MERRF) syndrome, accounted for in most cases by the mitochondrial tRNA(Lys) A8344G mutation (Chong et al., 2003). These observations led to the suggestion that mitochondrial dysfunction may be an important pathogenic factor in MSL. In 2015, a homozygous missense mutation, p.Arg707Trp, was identified in MFN2, or mitofusin 2, in three patients with MSL and neuropathy from two families (Sawyer et al., 2015). Mitofusin 2 is a nucleus-encoded mitochondrial outer membrane protein involved in mitochondrial fusion, mitochondrial interactions with the endoplasmic reticulum (Naon et al., 2016), and other aspects of cellular metabolism (de Brito and Scorrano, 2008; Zorzano et al., 2015). Arg707 lies in the carboxy-terminal coiled coil domain HR2 of mitofusin 2 that is believed to be critical for homotypic and heterotypic interactions of mitofusin 2 (Franco et al., 2016; Koshiba et al., 2004) with counterparts on other organelles, leading to the suggestion that the p.Arg707Trp mutation may compromise outer mitochondrial membrane fusion (Sawyer et al., 2015).

MFN2 p.Arg707Trp is the only reported cause of Mendelian MSL to date, however the nature of the associated adipose pathology, and the mechanism linking this mutation to MSL is unknown. We now describe four further patients with MSL associated with biallelic MFN2 mutations, in all cases including at least one p.Arg707Trp allele, investigate key aspects of their intermediary metabolism, and examine the microscopic and transcriptomic derangements in affected adipose tissue. We thereby provide a monogenic example of primary, apparently tissue-selective mitochondrial dysfunction leading to insulin resistance, and describe a form of leptin deficiency in the face of severe upper body obesity. Our findings yield novel insights into the role of mitofusin 2 in adipocyte energy metabolism and proliferation in humans in vivo, and suggest targeted treatments for MSL that warrant further assessment.

MSL is a phenotypically dramatic condition that has been known since the nineteenth century. Understanding of its pathogenesis is likely to yield insights into poorly understood aspects of adipose tissue function that are critical to pandemic diseases, including the determinants of the differing metabolic behaviours of different adipose depots. Study of MSL has been hampered, however, by its clinical heterogeneity, and lack of knowledge of its cause (Herbst, 2012). The recent report of homozygosity for the MFN2 p.Arg707Trp mutation in three individuals with MSL (Sawyer et al., 2015) suggested the first germline Mendelian cause of the disorder, presenting a critical opportunity to further understanding of the underlying pathogenesis, however the pathology of the overgrown adipose tissue and the systemic metabolic consequences were not specifically studied. We now describe four more affected patients, confirming the genetic association, demonstrate that increased adipose mass is accounted for by hyperplasia of UCP1-negative, unilocular adipocytes, and provide evidence of mitochondrial dysfunction in affected adipose tissue. We also show that depot-selective adipose hyperplasia is discordant with suppressed leptin levels and impaired insulin-mediated suppression of lipolysis in severely affected patients, while insulin resistance is seen in all. These findings offer a new window into the extraordinary depot-selective adipose overgrowth of MSL, and offer new opportunities for novel therapy, and to gain insights into fundamental aspects of adipocyte behaviour crucial to pandemic disease.

Bioenergetic efficiency and ATP-generating capacity of mitochondria are heavily influenced by the dynamic architecture of the mitochondrial network (eg. [Liesa and Shirihai, 2013; Mishra and Chan, 2016]). This is regulated by specialised proteins including mitofusin 2 (Schrepfer and Scorrano, 2016), which is important not only in mitochondrial fusion, but also in mitochondrial-ER tethering (Naon et al., 2016), apoptosis (de Brito and Scorrano, 2008), mitophagy (Chen and Dorn, 2013) and regulation of the unfolded protein response (Pablo Muñoz et al., 2014). Global knockout of Mfn2 in mice is embryonically lethal (Chen et al., 2003), but knockout specific to cardiac or skeletal muscle (Chen and Dorn, 2013; Sebastián et al., 2016), to dopaminergic neurones (Pham et al., 2012), to the renal proximal tubule (Gall et al., 2015), or to POMC neurones of the hypothalamus (Schneeberger et al., 2013) is tolerated. Nevertheless in each case cell or organ dysfunction is seen. Together with evidence that MFN2 expression is lowered in key metabolic tissues in disease states (Schneeberger et al., 2013; Zorzano, 2009), this has led to keen interest in mitofusin 2 as a contributor to the pathogenesis of pandemic obesity-related diseases. No adipose-specific knockout has been described.

Despite this largely murine evidence for important roles of MFN2 in several tissues, MFN2 loss-of-function mutations in humans have until recently been implicated solely in axonal sensorimotor neuropathy (Züchner et al., 2004), which is only weakly recapitulated in mouse models (Detmer et al., 2008; Strickland et al., 2014). Our findings, together with those of Sawyer et al. (2015), now highlight a second tissue-selective phenotype in humans, namely severe upper body adipose overgrowth or ‘Multiple Symmetrical Lipomatosis’ (MSL). All cases of MFN2-related MSL have featured biallelic mutations including at least one MFN2 p.Arg707Trp allele, and many, but not all, patients have shown early-onset neuropathy in addition. Our structural analysis suggests that the mutation may have differential effects on different conformations of MFN2, particularly trans-dimerisation and thus membrane fusion. It may be important that MFN2 homodimers will be most affected (Figure 1E) as both surfaces at the interface have a mutation, while in heterodimers only one surface is mutated. The second mutation we report in P1, who is severely affected, is predicted significantly to impair or to abrogate MFN2 function by destroying the helical support of the hinge between the GTPase and stalk domains (Figure 1C). Although the association of the MFN2 p.Arg707Trp mutation specifically with MSL is striking, existing human genetic data do not exclude the possibility that other HR2 domain mutations may also lead to the phenotype when both MFN2 alleles are affected.

The overgrown adipose tissue is unable to execute its key metabolic functions normally, as evidenced by insulin resistance, and reduced suppression of circulating free fatty acid concentrations after a glucose load. One caveat to this assertion is that it is possible that the ‘lipodystrophic’ or triglyceride-depleted lower limb adipose depots might also be contributing to the perturbed suppression of lipolysis and insulin resistance. Most strikingly, despite dramatic upper body adipose overgrowth in MFN2–related MSL, adipose tissue expression of the archetypal adipocyte hormones leptin and adiponectin was extremely low, with P1, P4 and one of the older, more severely affected patients previously described having undetectable plasma leptin despite high fat mass (Sawyer et al., 2015). We hypothesize that the differences observed in leptin concentrations among the patients we describe reflects the evolution of the disease, with all adipose depots affected either by overgrowth (upper body) or dystrophy (lower body) in P1 and P4, while in P2 and P3 some normal adipocytes remain. We suggest that advanced MFN2-related MSL represents a fourth form of severe leptin deficiency in humans, adding to congenital LEP mutations, lack of adipocytes in generalised LD, and ‘empty’ adipocytes in extreme leanness or starvation. We note that this phenotype may not be present in all MSL cases, as others have reported normal leptin levels in MSL cases of undefined cause (Haap et al., 2004).

Suppressed leptin expression could be explained if the pathologically expanding cell lineage had naturally low levels of leptin expression, as reported for brown adipocytes, or alternatively may reflect perturbation of a cellular mechanism sensing mitochondrial function and cellular energy state and transducing it into leptin gene expression. Although we demonstrate that increased adipose mass is accounted for by hyperplasia of cells with morphologic and transcriptional characteristics of UCP1-negative, unilocular white adipocytes, we cannot rule out the possibility that these cells are dysfunctional, ‘whitened’ thermogenic adipocytes, and indeed mitochondrial depletion has previously been shown to be involved in ‘whitening’ of beige adipocytes (Altshuler-Keylin et al., 2016).

Evidence of impaired mitochondrial function in MFN2-related MSL is seen in strikingly elevated blood lactate concentrations in P1, P4 and previously described patients (Sawyer et al., 2015), reduced expression of citrate synthase and respiratory chain components, and highly abnormal mitochondrial ultrastructure in affected adipose depots. The reduction in mitochondria-encoded transcripts, contrasting with increased nucleus-encoded mitochondrial transcripts and mitochondrial biogenesis factors suggests that compensatory transcriptional programmes are activated to try to restore cellular mitochondrial function. In contrast, gene expression, and mitochondrial morphology and fusion of primary dermal fibroblasts is normal, confirming mitochondrial dysfunction in MFN2-related MSL to be tissue-selective, and suggesting that MFN2 Arg707Trp remains able to mediate mitochondrial fusion in some contexts.

Affected adipose tissue shows strong and consistent evidence of activation of mitochondrial stress responses, with notably strong upregulation of genes known to be positively regulated by ATF4 and CHOP (e.g. TRB3, ATF5, PSAT1, CHAC1, HSPA5 (BiP), SLC7A5, SLC7A11) (Han et al., 2013) or mTORC1 signaling. ATF4 and CHOP activities and expression are upregulated by PERK, which mediates a key arm of the ER unfolded protein response, and has also been shown to interact directly with MFN2 at ER-mitochondrial junctions (Naon and Scorrano, 2014; Pablo Muñoz et al., 2014), while ATF5 has recently been suggested to be the mammalian counterpart of the C. elegans mitochondrial unfolded protein sensor ATFS-1 (Fiorese et al., 2016). mTORC1 may be activated either downstream or upstream from the UPR (Appenzeller-Herzog and Hall, 2012), driving protein synthesis, especially of nucleus-encoded mitochondrial genes (Morita et al., 2013).

Increased cell proliferation or survival in the face of mitochondrial dysfunction is not unprecedented: The phenomenon of mitohormesis (Yun and Finkel, 2014), whereby mild mitochondrial dysfunction exerts pro-survival effects on cells and organisms, is well established in model systems. MSL is also associated with other forms of genetic or acquired mitochondrial insult, including a common mitochondrial lysyl tRNA mutation (Chong et al., 2003), HIV infection treated with highly active anti-retroviral therapy (Giralt et al., 2011), and excess alcohol intake (Enzi et al., 2015). This raises the possibility that in MFN2-related MSL mitochondrial dysfunction falls in a narrow window of severity that drives mitohormetic upper body preadipocyte differentiation and/or reduced adipocyte clearance. Whether lower body adipocytes are relatively less unaffected, and thus depleted of triglyceride stores as a ‘bystander’ effect of pathologically expanding upper body adiposity, or whether they are more severely affected and thus die in the face of the same genetic insult, remains to be determined.

Arguing against a critical role for a general reduction in mitochondrial function as the critical driver of MSL, the overwhelming majority of known forms of monogenic mitochondrial dysfunction, of varying severity, are not associated with it, suggesting an alternative, or additional, specific effect of the MFN2 mutations observed. This is plausible as MFN2 deficiency has been shown in cellular contexts to suppress apoptosis (Pablo Muñoz et al., 2014; Shen et al., 2007), and in ischemic hearts and kidneys to reduce ischaemic tissue (Hall et al., 2016; Pablo Muñoz et al., 2014) damage and cell death. MFN2-related MSL could thus reflect a dyscoordinated cellular stress response to severe mitochondrial dysfunction, with MFN2 mutations preventing cell death, allowing survival and proliferation of functionally impaired cells.

Finally, our findings have potentially important implications for therapy. Hypogonadism and hyperphagia related to absolute leptin deficiency in P1 may respond to subcutaneous leptin therapy, reducing the burden imposed on overgrown adipose tissue by chronic positive energy balance, while the effect of inhibiting the upregulated anabolic pathways detected transcriptomically, such as mTOR signalling, using clinically available inhibitors, is worthy of consideration. This is in keeping with the promise shown by sirolimus in murine mitochondrial disease (Johnson et al., 2013).

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Author details

1. Nuno Rocha

   1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
   2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

   Contribution

   NR, Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared.

2. David A Bulger

   1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
   2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
   3. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States

   Contribution

   DAB, Formal analysis, Investigation, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared.

3. Andrea Frontini

   Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy

   Contribution

   AF, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared.

4. Hannah Titheradge

   1. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
   2. West Midlands Medical Genetics Department, Birmingham Women’s Hospital, Edgbaston, Birmingham, United Kingdom

   Contribution

   HT, Conceptualization, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared.

5. Sigrid Bjerge Gribsholt

   Department of Endocrinology and Internal Medicine and Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

   Contribution

   SBG, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared.

6. Rachel Knox

   1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
   2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

   Contribution

   RK, Resources, Investigation, Writing—review and editing, final approval of the version to be published

   Competing interests

   No competing interests declared.

7. Matthew Page

   New Medicines, UCB Pharma, Slough, United Kingdom

   Contribution

   MP, Formal analysis, Writing—review and editing, final approval of the version to be published

   Competing interests

   No competing interests declared.

8. Julie Harris

   1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
   2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

   Contribution

   JH, Resources, Investigation, final approval of the version to be published

   Competing interests

   No competing interests declared.

9. Felicity Payne

   Wellcome Trust Sanger Institute, Cambridge, United Kingdom

   Contribution

   FP, Formal analysis, Writing—review and editing, final approval of the version to be published

   Competing interests

   No competing interests declared.

10. Claire Adams

    1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
    2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

    Contribution

    CA, Resources, Investigation, final approval of the version to be published

    Competing interests

    No competing interests declared.

11. Alison Sleigh

    1. Wolfson Brain Imaging Centre, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom
    2. National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom

    Contribution

    AS, Formal analysis, Investigation, final approval of the version to be published

    Competing interests

    No competing interests declared.

12. John Crawford

    Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom

    Contribution

    JC, Resources, Writing—review and editing, final approval of the version to be published

    Competing interests

    No competing interests declared.

13. Anette Prior Gjesing

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Contribution

    APG, Formal analysis, Investigation, Writing—review and editing, final approval of the version to be published

    Competing interests

    No competing interests declared.

14. Jette Bork-Jensen

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Contribution

    JB-J, Formal analysis, Investigation, Writing—review and editing, final approval of the version to be published

    Competing interests

    No competing interests declared.

15. Oluf Pedersen

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Contribution

    OP, Supervision, Funding acquisition, Writing—review and editing, final approval of the version to be published

    Competing interests

    No competing interests declared.

16. Inês Barroso

    Wellcome Trust Sanger Institute, Cambridge, United Kingdom

    Contribution

    IB, Formal analysis, Supervision, Writing—review and editing, final approval of the version to be published

    Competing interests

    No competing interests declared.

    "This ORCID iD identifies the author of this article:" 0000-0001-5800-4520

17. Torben Hansen

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Contribution

    TH, Supervision, Funding acquisition, Writing—review and editing, final approval of the version to be published

    Competing interests

    No competing interests declared.

18. Helen Cox

    West Midlands Medical Genetics Department, Birmingham Women’s Hospital, Edgbaston, Birmingham, United Kingdom

    Contribution

    HC, Resources, Writing—review and editing, Acquired data

    Competing interests

    No competing interests declared.

19. Mary Reilly

    MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom

    Contribution

    MR, Resources, Writing—review and editing, Final approval of the version to be published

    Competing interests

    No competing interests declared.

20. Alex Rossor

    MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom

    Contribution

    AR, Resources, Writing—review and editing, Final approval of the version to be published

    Competing interests

    No competing interests declared.

21. Rebecca J Brown

    National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States

    Contribution

    RJB, Writing—review and editing, Acquired data; final approval of the version to be published

    Competing interests

    No competing interests declared.

22. Simeon I Taylor

    University of Maryland School of Medicine, Baltimore, United States

    Contribution

    SIT, Writing—review and editing, Acquired data; final approval of the version to be published

    Competing interests

    No competing interests declared.

23. Duncan McHale

    New Medicines, UCB Pharma, Slough, United Kingdom

    Contribution

    DM, Supervision, Funding acquisition, Writing—review and editing, Final approval of the version to be published

    Competing interests

    No competing interests declared.

24. Martin Armstrong

    New Medicines, UCB Pharma, Slough, United Kingdom

    Contribution

    MA, Formal analysis, Writing—review and editing

    Competing interests

    No competing interests declared.

25. Elif A Oral

    Metabolism, Endocrinology and Diabetes (MEND) Division, Department of Internal of Medicine, Brehm Center for Diabetes, Ann Arbor, United States

    Contribution

    EAO, Data curation, Writing—original draft, Writing—review and editing

    Competing interests

    EAO: Receives grant and consultant fees from Aegerion Pharmaceuticals, and Akcea Therapeutics, scientific advisory board member for AstraZeneca, nonmaterial support from Aegerion Pharmaceuticals and Boehringer Ingelheim. None of these are pertinent for the work here.

26. Vladimir Saudek

    1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
    2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

    Contribution

    VS, Formal analysis, Writing—original draft, Writing—review and editing

    Competing interests

    No competing interests declared.

27. Stephen O’Rahilly

    1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
    2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

    Contribution

    SO’R, Supervision, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared.

28. Eamonn R Maher

    1. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
    2. Department of Medical Genetics, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom

    Contribution

    ERM, Conceptualization, Supervision, Investigation, Writing—original draft, Writing—review and editing

    Contributed equally with

    Bjørn Richelsen

    For correspondence

    erm1000@medschl.cam.ac.uk

    Competing interests

    No competing interests declared.

29. Bjørn Richelsen

    Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Clinical Medicine, Aarhus University, Aarhus, Denmark

    Contribution

    BR, Conceptualization, Supervision, Investigation, Writing—original draft, Writing—review and editing

    Contributed equally with

    Eamonn R Maher

    For correspondence

    bjoern.richelsen@aarhus.rm.dk

    Competing interests

    No competing interests declared.

30. David B Savage

    1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
    2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

    Contribution

    DBS, Conceptualization, Formal analysis, Funding acquisition, Investigation, Writing—original draft, Writing—review and editing

    For correspondence

    dbs23@medschl.cam.ac.uk

    Competing interests

    No competing interests declared.

31. Robert K Semple

    1. The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom
    2. The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom

    Contribution

    RKS, Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Writing—original draft, Writing—review and editing

    For correspondence

    rks16@cam.ac.uk

    Competing interests

    No competing interests declared.

    "This ORCID iD identifies the author of this article:" 0000-0001-6539-3069

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