Review Article

Overview of human obesity and central mechanisms regulating

energy homeostasis

Vivion E F Crowley
Central Pathology Laboratory, Department of Biochemistry, St James’s Hospital, Dublin 8, Ireland
Email: vcrowley@stjames.ie
This article was prepared at the invitation of the Clinical Sciences Reviews Committee of the Association for Clinical Biochemistry.

Abstract
Obesity is now regarded as a global epidemic affecting both adults and children, and is associated with significant morbidity
and mortality. Thus the effective management of obesity has become an important clinical focus. Therefore, an understanding
of the pathways controlling appetite, satiety and food intake is critical for gaining an insight into the pathogenesis of obesity
and also for the development of diagnostic tests and therapeutic agents for use in the clinical management of this condition.
Over the last decade or more research using both mouse and human genetic models has elucidated the critical role of the
leptin-melanocortin pathway in the hypothalamus, in regulating mammalian energy balance. In tandem with this, a clearer
understanding of the regulation of gut-derived hormones and their interaction with the central nervous system has further
illuminated the complex interplay between central and peripheral aspects of energy regulation. The obesity epidemic and the
expanded knowledge base relating to its aetiopathogenesis have specific implications for clinical biochemistry. In particular,
an increase in workload may be expected due to biochemical investigation of obesity and its co-morbidities. Moreover, advice
on the in-depth investigation of complex cases of obesity may be sought, including information on newer diagnostic tests,
such as serum leptin or molecular genetic analysis. There may also be a substantive role for chemical pathologists in
establishing and running clinical obesity services. Finally, clinical biochemistry has a role in research pertaining to obesity and
cardiometabolic risk.

Ann Clin Biochem 2008; 45: 245– 255. DOI: 10.1258/acb.2007.007193

Introduction higher risk for developing certain cancers, e.g. endometrial,

It is now almost universally acknowledged that obesity is a
major leading public health issue. In the USA, over 60% of
adults are now considered overweight and over 30% are
clinically obese.1 Moreover, the prevalence rates in many
European countries, including the UK and Ireland, are
rapidly approaching the levels encountered in the USA.2
In general, it is suggested that up to 20% of the population
of most Western countries are obese, with up to 50% classi-
fied as overweight. Moreover, this problem is not only con-
fined to Western societies and the World Health
Organization (WHO) has proclaimed obesity to be a
global epidemic.3
While there are obvious cosmetic and quality-of-life
issues related to obesity, the primary focus in the realm of
health care is on the substantial morbidity and mortality
associated with this condition (Table 1). Clinical problems
range from mechanical, such as osteoarthritis and sleep
apnoea, to metabolic perturbations resulting in type 2 dia-
betes (T2DM), hyperlipidaemia, hypertension and an
overall increased cardiovascular risk.4 In addition, there is
an increasing realization that obesity is associated with a
colon and prostate.5
The marked increase in obesity prevalence has prompted
a number of government-led reviews of this health problem
in many countries, with the intended remit of preventing
the occurrence of obesity and also developing effective clini-
cal management strategies to tackle the clinical ramifications
of this disease.6,7 Such initiatives will have important down-
stream implications for many areas of the health-care sector,
including laboratory medicine.
Measurement of obesity
There are many different methods applied to the classifi-
cation of obesity and the measurement of adiposity. The
WHO classification, which is the most widely applied in
clinical practice, is based on the measurement of body
mass index (BMI) (weight/height2).8 In this system, over-
weight is defined as BMI 25 kg/m2, while obesity is deter-
mined by BMI 30 kg/m2 (Table 2). However, there are
caveats in relation to universal application of this classifi-
cation because of differences observed in the relationship

Annals of Clinical Biochemistry 2008; 45: 245– 255

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246 Annals of Clinical Biochemistry Volume 45 May 2008
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Table 1 Health consequences of obesity Table 3 Diagnostic criteria for the metabolic (insulin resistance)
syndrome
Metabolic/Cardiovascular Miscellaneous
Abdominal obesity WC . 102 cm (male)
Type 2 diabetes mellitus Cancer
WC . 88 cm (female)
Insulin resistance Gallbladder disease
Hypertriglyceridaemia .1.7 mmol/L
Dyslipidaemia Reflux oesophagitis
Low HDL-cholesterol ,1.0 mmol/L (male)
Hypertension Osteoarthritis
,1.3 mmol/L (female)
Cardiovascular disease Low back pain
Hypertension  130/85 mmHg
Congestive heart failure Sleep apnoea
High fasting glucose  6.1 mmol/L
Hyperuricaemia/Gout Non-alcoholic fatty liver disease
Polycystic ovarian syndrome Psychological illness The presence of three or more of these factors defines a subject as having
Impaired fertility metabolic syndrome. WC, waist circumference

severely impact in the future on already overstretched

between morbidity and BMI in various ethnic populations.
health service resources in many countries.
Thus, attempts are being made to adopt population or eth-
In children, different criteria are applied to the definition
nicity specific classifications of overweight and obesity
of overweight and obesity. It is recommended that a BMI
using BMI.
.95th percentile represents obesity, while a BMI .85th per-
Another limitation of BMI is that it is not a specific
centile is classified as overweight.13 Population-specific BMI
descriptor for the distribution of adipose tissue. This has
percentile charts should be derived for this purpose.
important clinical implications in view of the fact that com-
pelling evidence now indicates that accumulation of visceral
adiposity has a particularly strong association with the
development of metabolic complications such as T2DM, Aetiopathology of obesity
hypertension and cardiovascular disease (CVD).9 This
A number of factors are thought to contribute to the dra-
aspect of adverse fat distribution is well represented by
matic increase in the prevalence of obesity observed over
measurement of waist hip ratio or waist circumference
the last two decades (Table 4). There has been an increase
(WC). Notably, the WHO has produced a gender-specific
in the per capita average energy supply worldwide, and
classification for visceral adiposity based on WC, and WC
the trend for the inclusion in modern diets of food with
is included in the list of National Cholesterol Education
greater saturated fat and sugar content leads to increased
Programme (NCEP) III criteria for metabolic syndrome
caloric intake.14 Lifestyle changes, including the adaptation
(Table 3).10
of a more sedentary lifestyle due to changes in working and
Other methods for the measurement of adiposity include
leisure time demands, are also contributing factors.15 The
anthropometry (multisite skin-fold thickness), bioelectrical
increasing reliance on motorized transport relative to
impedance, imaging modalities such as magnetic resonance
cycling and walking is another potential factor.15,16 In
imaging (MRI) and dual energy X-ray absorptiometry
general, there are many other more subtle behavioural and
(DEXA) scanning and isotopic tracer measurements.11
environmental influences that contribute to this ‘obesogenic’
These techniques are likely to be available in specialist
milieu.15
obesity outpatient clinics and research facilities.
There is also now compelling evidence of a role for
genetic influences on body fat mass and BMI.17,18
Extensive family, twin and adoption studies all support
the notion that adiposity is a highly heritable trait and
Childhood obesity
A serious consequence of the current obesity epidemic is the Table 4 Aetiology of human obesity
alarming increase in the prevalence of childhood-onset Primary
obesity.12 In addition, co-morbidities such as T2DM, and Polygenic obesity (gene– environment-behavioural interactions)
features consistent with the metabolic syndrome, e.g. low Secondary
plasma HDL-cholesterol, are now emerging in this Endocrine Cushing’s syndrome
Hypothyroidism
cohort.12 The phenomenon of childhood obesity is a Hypopituitarism
portent to a potential health-care deluge, which will Drug-induced Steroids
Insulin
Thiazolidinediones
Table 2 World Health Organization classification of weight using
Phenothiazines
body mass index (BMI) (1995)
Sodium valproate
Classification BMI (kg/m2) Hypothalamic Tumour
Radiation
Underweight ,18.5
Trauma
Reference range 18.5 – 24.9
Postoperative
Overweight 25.0
Genetic syndromes Prader-Willi
Pre-obese 25.0 – 29.9
Alstrom
Obese Class I 30.0 – 34.9
Bardot-Biedl
Obese Class II 35.0 – 39.9
Monogenic
Obese Class III 40.0

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 Crowley. Overview of human obesity and central mechanisms
................................................................................................................................................
direct estimates of heritability vary from 40 to 70%.17 Thus,
the paradigm that should be applied in relation to common
or polygenic obesity is that it is a phenotype which results
primarily from gene –environment interactions.
There are some circumstances where obesity has a clear
organic or genetic origin.19 Thus, many commonly used
drugs, e.g. insulin, corticosteroids, can increase body
weight. Many endocrine and neuroendocrine diseases are
associated with weight gain, e.g. Cushing’s syndrome,
hypothalamic disease and injury. Certain pleiotrophic
genetic syndromes, e.g. Prader-Willi, Alstrom syndrome,
may have obesity as a feature, and in the last decade the
emergence of specific monogenic syndromes of obesity
have been reported.20
The control of appetite and satiety
In simple thermodynamic terms, obesity can be considered
as a chronic disorder of energy imbalance, in which a long-
term excess of energy intake over expenditure leads to the
storage of that excess energy as adipose tissue.21
Therefore, a central focus in the effort to elucidate the aetio-
pathogenesis of obesity and weight gain is the attempt to
illuminate the complex neuromolecular mechanisms which
underlie the regulation of mammalian energy homeostasis.
The role of the hypothalamus in
energy homeostasis
The critical role of the hypothalamus in regulating energy
intake was finally established over 50 years ago with the
classic experiments of Hetherington and Ranson,22 who
placed electrolytic lesions in the rat hypothalamus.
Affected animals developed a ‘condition of marked
adiposity’. These elegant experimental systems served as a
basis for investigating the neural networks operating in
the relevant areas of the hypothalamus for many sub-
sequent years. More recently, the delineation of specific
molecular genetic defects in well characterized, naturally
occurring rodent genetic models of obesity has also facili-
tated the development of a comprehensive hard wire
neural map of the appetite and satiety regulatory pathways
within the mammalian central nervous system (CNS)
(Figure 1).23 – 28 Furthermore, the identification of ortholo-
gous genetic defects in human subjects with severe obese
phenotypes has provided bona fide evidence of the import-
ance and relevance of these pathways in humans.29 – 33
For many years, the existence of a circulating factor
linking central hypothalamic appetite regulatory pathways
and adipose tissue was proposed. The breakthrough in
identifying this lipostatic hormone occurred with the dis-
covery of leptin, and the recognition that leptin deficiency
was the basis for obesity observed in the ob/ob mouse,
an extensively studied rodent model of obesity.23 Leptin is
an adipocyte-derived hormone secreted in response to an
increase in energy stores and thus its concentrations in
plasma are directly proportional to the degree of body
fat.34 The primary action of leptin in rodents is to exert a
long-acting effect of reducing adiposity by attenuating
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247
Higher CNS centres
Anorexigenic Autonomic NS Orexigenic
pathways pathways
CRF
MSH Second order
PVN TRH LHA neurons
Orexin A, B
GLP-1
- -
+ +
ARC
NPY/AGRP POMC/CART First order
Neurons Neurons neurons
– +
Leptin
Insulin
Figure 1 Hypothalamic networks implicated in the control of food intake.
AGRP, Agouti-related protein; ARC, arcuate nucleus; CART, cocaine and
amphetamine regulated transcript; CRF, corticotrophin releasing factor;
GLP-1, glucagon-like peptide-1; LHA, lateral hypothalamic area; MSH, mela-
nocyte-stimulating hormone; NPY, neuropeptide Y; POMC, proopiomelano-
cortin; PVN, paraventricular nucleus; TRH, thyrotrophin-releasing hormone;
NS, nervous system; CNS, central nervous system
appetite and increasing thermogenesis. Two forms of
leptin receptor (LEPR) have been identified, a long form
(OB-RL) which appears to mediate leptin signal transduc-
tion, and a short form (OB-RS), which is thought to facilitate
transport across the blood – brain barrier.34,35 OB-RL is a
member of the cytokine receptor family, and activates the
JAK/STAT signal pathway, which employs Janus kinases
(JAKs) and signal transducers and activators of transcrip-
tions (STATs).
Molecular mapping of the effects of leptin on the hypo-
thalamus and other areas of the CNS was performed by
studying the expression of immediate early genes, particu-
larly c-fos, after both systemic and intracerebroventricular
(ICV) administration of leptin.36 Leptin directly modulated
neuropeptide expression in so-called first-order neurons in
the hypothalamic arcuate nucleus (ARC), and these
neurons in turn regulated, by synaptic input, neuropeptide
expression in downstream neurons (second-order neurons
or higher). After extensive study it is now apparent that
the primary first-order neuronal targets of leptin (and
insulin) action are catabolic proopiomelanocortin (POMC)/
cocaine and amphetamine-regulated transcript (CART)
neurons, which are stimulated by lipostatic hormones, e.g.
leptin, and anabolic neuropeptide Y (NPY)/Agouti-related
protein (AGRP) neurons which are suppressed by
leptin.36 – 38
In the currently accepted neuroanatomical framework,
POMC/CART neurons project from the dorsolateral ARC to
a number of second-order neurons in locations such as the
lateral hypothalamic area (LHA) and the paraventricular
nucleus (PVN). In the LHA, they appear to make monosynap-
tic connections with neurons expressing melanocortin-
stimulating hormone (MSH) and orexins A and B, suppressing
the expression of these neuropeptides. MSH is a particularly
potent orexigenic molecule, and ICV injection into normal
248 Annals of Clinical Biochemistry Volume 45 May 2008
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rodents leads to a marked increase in food intake.39 In the
PVN, which tends to have a primarily catabolic output
(compared with the anabolic output of LHA), POMC
neurons interact with second-order neurons expressing
thyrotropin-releasing hormone (TRH), corticotrophin-
releasing hormone (CRH) and oxytocin. Both TRH and
CRH have been demonstrated to enhance energy expendi-
ture while decreasing caloric intake. These effects may be
mediated, in part, through the thyroid axis and the sym-
pathetic nervous system.
The NPY/AGRP neurons are concentrated in the ventro-
medial ARC and also project to the LHA and PVN.36 – 38
NPY is a highly abundant peptide in the hypothalamus and
has the powerful effect of increasing food intake when admi-
nistered centrally.40 Moreover in the ob/ob mouse, the absence
of NPY does appear to partially ameliorate the obese pheno-
type caused by congenital leptin deficiency.41
Finally, as well as communications within the hypothala-
mus, the POMC/CART and the NPY/AGRP also communi-
cate directly with neural pathways and clusters in other
areas of the CNS, such as the nucleus of the solitary tract
(NTS) in the brainstem, which has been implicated as a princi-
pal target of short-acting meal termination signals, e.g. mech-
anical gastric stretch, cholecystokinin (CCK) and glucagon-like
peptide-1 (GLP-1). Overall, the regulation of energy balance
involves a complex network of multiple interacting neuron
populations from distinct areas of the CNS.36 – 38
Melanocortin system
A substantial body of both genetic and pharmacological
research data clearly implicates the melanocortin system as
a nodal point in the control of appetite and energy
balance.42,43 While POMC expression is upregulated in
response to leptin and increased energy stores, POMC
expression in ARC is reduced in conditions such as fasting
or leptin deficiency.44 POMC is post-translationally
cleaved, most probably by prohormone convertase 1 (PC1)
into multiple peptides which include a-, b- and g-MSH.45
In the CNS, two of the five known melanocortin receptors
(MCR), namely MC3R and MC4R, are highly expressed in
areas of the brain concerned with the regulation of food
intake, e.g. PVN, LHA and autonomic activity.46,47 The
MC4R has a high affinity for the agonists a- and b-MSH,
but also has a strong affinity for the naturally occurring
antagonist AGRP. Thus, it seems that MC4R is a point in
the hypothalamus at which fine tuning of the leptin signal
cascade takes place, with the relative balance between
agonist (MSH) and antagonist (AGRP) determining the
effect transduced.48 Indeed, the administration of low-dose
MC4R antagonists attenuates significantly the capacity of
exogenously administered leptin to reduce food intake.49
In addition, deletion of MC4R gene in mice results in a phe-
notype characterized by early-onset hyperphagia and
obesity.33 The importance of the melanocortin pathway in
promulgating the leptin signal cannot be overstated.
Insights from human monogenic
syndromes of obesity
While the extensive study and unravelling of the molecular
defects in rodent models of obesity confirmed the critical
nature of the leptin-melanocortin system in mammalian
energy regulation, it remained to be determined whether
the importance of this control pathway could be extrapo-
lated to the more complex biological systems operating in
humans (Table 5). Through the identification of a number
of monogenic disorders, in which early-onset obesity is a
pre-eminent phenotype, the relevance of the leptin-
melanocortin pathway to human appetite regulation was
firmly established.29 – 33,50,51
Within a few years of the discovery of leptin and its role in
the pathogenesis of obesity in the ob/ob mouse model, the
first human cases of congenital leptin deficiency were
described by O’Rahilly’s group in the University of
Cambridge, UK.29 Two severely obese cousins from a
highly consanguineous family of Pakistani origin were
found to be homozygous for a frameshift mutation (DG
133) in the LEP gene.29 This resulted in the production of
a truncated protein, which was not secreted and, thus,
despite their obesity, plasma leptin concentrations were
paradoxically undetectable in these subjects.52
Subsequently, four other affected individuals from three
different Pakistani kindreds, who are also homozygous for
the same mutation, were identified. This suggests either
that the mutation is a founder mutation in this ethnic
group or that the area of the LEP gene affected, which con-
tains a sequence of six guanines, is a mutation hotspot. A

Table 5 Monogenic causes of human obesity

Gene Gene product Location Clinical phenotype References
LEP Leptin 7q31.3 Early-onset severe obesity; hyperphagia with no macronutrient preference; 29, 53 –56
impaired T-cell mediated immunity; hypogonadotrophic hypogonadism
LEPR Leptin receptor 1p31 Early onset severe obesity; hypogonadotrophic hypogonadism; central 30
hypothyroidism; moderate growth hormone impairment
POMC Proopiomelanocortin 2p23.3 Early-onset obesity; pale skin and red hair; adrenocorticotropic hormone (ACTH) 32
deficiency
PC-1 Prohormone convertase 1 5q15-21 Extreme childhood-onset obesity; hypogonadotrophic hypogonadism; ACTH/ 31, 61
cortisol deficiency; abnormal prohormone processing, e.g. gut hormones,
insulin; malabsorption and diarrhoea
MC4R Melanocortin 4 receptor 18q21.3 Childhood-onset obesity with hyperphagia; accelerated linear growth; increased 33, 50, 51
age-related bone mineral density; hyperinsulinaemia; obesity in adulthood
NTRK2 Neurotrophin receptor 9q22.1 Severe hyperphagic obesity; learning disability and complex developmental 71
tyrosine kinase B abnormalities

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 Crowley. Overview of human obesity and central mechanisms
................................................................................................................................................
Turkish kindred has also been identified in which a different
missense mutation (A105W) is pathogenic for this
condition.53
A clear phenotype associated with human congenital
leptin deficiency has emerged.54 – 56 Affected subjects
are characterized by severe early childhood-onset obesity
and marked hyperphagia. In addition, hyperinsulinaemia
and advanced bone age are noted, and in adults hypogona-
dotrophic hypogonadism is a feature, although in one adult
subject spontaneous puberty did occur but was delayed.
Overall, most of the phenotypes manifest in ob/ob mice are
recapitulated in the humans. However, species-specific phe-
notypic differences were evident in that humans did not
present with certain features, including growth retardation,
hypercortisolaemia and reduced energy expenditure.54
Consistent with the observed profound anti-obesity effect
of leptin in ob/ob mice,57 leptin replacement in congenital
leptin-deficient subjects also produced a dramatic
response.54,55 Daily subcutaneous injections of leptin sub-
stantially reduced body weight, with 98% of weight loss
occurring in fat mass, this effect being evident in both chil-
dren and adult leptin-deficient subjects. The principal action
of leptin involved a significant attenuation of hyperphagia
and associated caloric intake. One female subject progressed
into puberty at the appropriate age, suggesting that leptin
replacement facilitated this action. Of note also, while
overt central hypothyroidism was not a clinical feature in
these patients, plasma-free T4 concentrations showed an
increase from the earliest post-treatment time point and
appeared to stabilize around a new concentration. This is
consistent with the observation that leptin has a role in
the regulation of TRH secretion from the hypothalamus.58
Thus, overall, leptin deficiency represents a form of mono-
genic obesity, which is directly amenable to mechanism-
based therapy.
A pathogenic mutation resulting in LEPR deficiency has
been described in a kindred of Algerian origin.30 Three
subjects with severe early-onset obesity were homozygous
for a splicing mutation (IVS16 þ1 G . A), which truncates
the LEPR before the transmembrane domain, thus result-
ing in an inability to transduce the leptin signal. The phe-
notype associated with this abnormality was very similar
to the ligand (leptin)-deficient state, however, certain
neuroendocrine features were noted which appeared
unique to LEPR deficiency, including impaired growth
hormone secretion with growth retardation, decreased
IGF-1 and IGF-BP3 plasma concentrations and overt
hypothalamic hypothyroidism. In addition, markedly
elevated leptin concentrations were observed, but this
may, in part, represent an effect related to high concen-
trations of circulating leptin bound to the truncated
LEPR rather than ‘leptin resistance’ per se. Recently, a
comprehensive report of the phenotype associated with
inherited LEPR deficiency indicated that normal concen-
trations of leptin are commonly observed in this
syndrome.59
Compelling evidence, which implicates POMC in human
energy balance, came from a report of two children har-
bouring loss of function mutations in this gene.32 The phe-
notype was characterized by a neonatal history of
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249
hypoadrenalism, childhood-onset obesity and hyperpha-
gia, with pale skin and red hair. Rather interestingly,
these phenotypic traits can be directly attributable to the
absence of an effect of specific POMC-derived peptides
on the requisite receptor. Thus, the hypoadrenalism is
related to a lack of adrenocorticotrophic hormone
(ACTH) action on MC2R, the obesity is the result of loss
of a-MSH action on MC4R, and the skin and hair traits
are a consequence of diminished a-MSH action on
MC1R. Whether the absence of other POMC-derived pep-
tides, such as b- and g-MSH or b-endorphin, contribute to
this phenotype in a subtle way remains to be determined,
although recent genetic studies suggest that this may be
the case for b-MSH.60
Further evidence in support of the key role of the melano-
cortin system in the regulation of body weight in humans
came from the identification of mutations in the PC1
gene.31,61 The phenotype observed in two reported cases,
both demonstrating compound heterozygosity for mutations
of this gene, included severe childhood-onset obesity due to
abnormal processing of POMC. Other features included
hypocortisolaemia, hypogonadotrophic hypogonadism,
postprandial hypoglycaemia and small intestinal dysfunc-
tion, all of which may be related to dysfunctional processing
of specific prohormone systems.
As indicated previously, the MC4R appears to function at
a critically important juncture in the leptin-mediated
pathway effecting mammalian energy homeostasis. The rel-
evance and importance of MC4R in human body weight
regulation has also now been confirmed by the identifi-
cation of several mutations in this gene, which is a highly
heterogeneous locus.30,50,51,62 – 64 In fact, mutations in the
MC4R gene represent the most common monogenic cause
of human obesity, with the prevalence of mutations
varying between 0.5 and 6.0% of obese subjects. The wide
variation in prevalence is, in part, related to selection criteria
used in individual studies, with the highest rates being
encountered in studies involving subjects with severe
early-onset obesity, as opposed to adult-onset disease.
Ethnic differences may also play some role in this discre-
pancy. The characteristic phenotype includes hyperphagia
beginning in childhood, accelerated linear growth, increased
age-related bone mineral density and hyperinsulinaemia.
Extensive phenotype– genotype studies indicate that the
degree of hyperphagia can be predicted by the severity of
receptor dysfunction caused by individual mutations in in
vitro reporter assays.65 In addition, the concentration of
hyperphagia appears to decline with age.65
While it was initially assumed that the mutations in
MC4R were dominantly inherited and had 100% pene-
trance, it is now apparent that a more complex mode of
inheritance is in operation. Thus, although some mutations
clearly demonstrate autosomal dominant inheritance, the
existence of kindred in which homozygotes for a MC4R
mutation manifest more severe obesity than heterozygotes
suggest that co-dominance, with modulation of expressivity
and penetrance, is a more appropriate method of describing
the inheritance pattern.65 It is likely that other genetic and
also environmental factors modulate the phenotypic
expression of MC4R.
250 Annals of Clinical Biochemistry Volume 45 May 2008
................................................................................................................................................

Leptin resistance in human obesity homeostasis, but the extent and nature of this partnership
has to be clarified. In addition, signalling through CNS, IR
In view of its dramatic effect of inducing loss of fat mass in
may modulate the metabolic effects of peripherally acting
rodents, leptin was, for a brief period after its discovery,
insulin in the liver and other target tissues.38
hailed as a major breakthrough in the treatment of
obesity. However, it was soon realized that circulating
leptin correlated with fat mass and BMI and, as a result, Additional central nervous system pathways
that obese individuals had elevated plasma leptin concen-
trations rather than reduced concentrations.66 Thus, There are an increasing number of other neurotransmitters
and neuropeptides, and their associated receptors, for
obesity in humans appeared to represent a form of ‘leptin
which a specific role in the control of food intake and
resistance’ and it was realized that attempts to use exogen-
overall energy balance has been proposed.48 In humans, ser-
ous leptin were unlikely to induce significant weight
otonin (5-HT) is a monoamine with many diverse CNS
reduction. Indeed, the results of early trials with recombi-
effects, including the process of satiation, and these effects
nant leptin bore out these considerations.67
A number of possible mechanisms have been posited to are mediated through at least 14 subtypes of receptor.
Brain-derived neurotrophic factor and its receptor TrkB
explain the state of leptin resistance in obesity.38 These
have also been implicated in the central regulation of
include, impaired leptin transport across the blood – brain
energy balance. Of note, a recent report described a child
barrier and the presence of negative regulators of leptin sig-
with a de novo mutation in NTRK2, the gene that encodes
nalling at the concentration of neurons in the CNS that
the neurotrophin receptor, TrkB. This mutation markedly
express LEPRs and their downstream targets. Recently, par-
ticular attention has focused on the negative regulatory role impaired receptor autophosphorylation and downstream
of suppressor of cytokine signalling 3 (SOCS3), which inhi- signalling, resulting in hyperphagic obesity and learning
disability.71
bits leptin signalling through the JAK/STAT pathway.68
Other neuropeptides and receptors with potential central
In relation to the concept of ‘leptin resistance’, it must be
effects on feeding include, CB1 cannabinoid receptor (CNR1)
borne in mind that leptin most likely plays its intended
and the endocannabinoids, anandamide and 2-arachidonoyl
physiological role at low concentrations and thus, at a
biological level, leptin may never have been intended to glycerol, interleukin-6 (IL-6), neuromedin U, ciliary neuro-
operate at the exorbitant plasma concentrations seen in trophic factor (CNTF), cortocotrophin releasing factor (CRF),
urocortin and orexins.48
obese subjects. The notion that the primary role of leptin
is to sense the transition between the starved and ade-
quately nourished state, rather than prevent obesity, is con- Gut hormones in the regulation
sistent with this idea.3 of energy balance
As indicated previously, leptin and insulin provide a mech-
Insulin as a lipostatic hormone anism by which adipose tissue can signal the hypothalamus

Prior to the discovery of leptin, it was proposed that insulin

may act as a sensor for energy stores between the periphery Hypothalamus
and the brain. Certainly, insulin fulfils many of the criteria Brainstem
associated with a lipostatic hormone.69 In particular, insulin ARC
can be transported across the blood – brain barrier in pro-
portion to body fat content, central administration is associ- NTS
ated with a reduction in food intake in mammals, and
insulin receptors (IRs) are located within the appetite regulat-
ory regions of the hypothalamus. Furthermore, insulin is a
key regulator of the switch between fasted and fed states,
and plasma concentrations decrease during fasting and
increase in obesity.
Further elucidation of insulin’s lipostatic role occurred
through the creation of mice with neuron-specific disruption
of the IR (NIRKO mice).70 While IR inactivation had no PYY (3-36) CCK + GLP-1 Ghrelin
effect on brain or neuronal development, these animals
did develop a diet-sensitive obesity associated with
increased body fat, mild hyperleptinaemia, insulin resist-
ance and hypertriglyceridaemia. Notably, the level of Small
obesity was mild in comparison with ob/ob mice and also Stomach
intestine
it is evident from leptin-deficient human subjects that
insulin cannot substantially compensate for the absence of
functioning leptin.
Figure 2 Sites of action of gut-derived signals influencing food intake. ARC,
Currently, it is considered that insulin acts in concert with arcuate nucleus; CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; NTS,
leptin to influence hypothalamic control of energy solitary nucleus; PYY3-36, peptide YY3-36

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 Crowley. Overview of human obesity and central mechanisms
................................................................................................................................................
and influence overall energy balance (Figure 2). However, it
is well recognized that the control of appetite is based on a
highly complex network of interactions and that signals
from the gastrointestinal tract can also impact on appetite
control and energy homeostasis.72 In particular, it has
been hypothesized that gut hormones play a significant
role in postprandial satiety.73
There is an abundance of research supporting the role of
CCK in mediating meal termination.74,75 In essence, the pre-
sence of luminal fat and protein stimulate the release of
CCK from duodenal mucosal cells. In turn, CCK activates
CCKA-type receptors located on peripheral vagal afferent
fibres, which transmit signals to the NTS in the brainstem
and the signal is relayed from this site to the hypothalamic
feeding centre.76,77 Of note, the effect of infused CCK is rela-
tively short-lived (30 min), which is consistent with its role
as a mediator of satiety and meal termination.77
GLP-1 is also implicated in appetite regulation, and is
derived from the cleavage of the precursor preproglucagon
in pancreas, intestinal L cells and the CNS.78 It is released
from the gut into the bloodstream in response to intestinal
nutrients and GLP-1 receptors are found in the brainstem
and hypothalamus (PVN and ARC).75,77 ICV administration
of GLP-1 suppresses appetite,79 while ICV injection of a
GLP-1 antagonist increases food intake.80 GLP-1 is also
recognized as an incretin, potentiating insulin secretion
from the pancreatic islets, and this may contribute to its
role in satiety.81 Overall, the biological importance of
GLP-1 as both incretin and neuropeptide remains controver-
sial and requires further elucidation.
Peptide YY (PYY) is co-secreted with GLP-1 from intesti-
nal L cells, primarily as the PYY3-36 form, in response to gut
nutrients.75,82 It is related to and has approximately 70%
amino acid homology with neuropeptide (NPY). However,
recent studies involving both rodent and human subjects,
have reported that peripheral administration of PYY3-36
leads to a marked inhibition of food intake in contrast to
the effects of NPY.83 – 85 Notably, these effects are not
observed in transgenic mice lacking the NPY Y2 receptors,
implicating this receptor as the mediator of the
PYY3-36-related anorectic action.83 Of note also is that
natural plasma concentrations of PYY3-36 were lower in
obese subjects compared with lean controls. These findings
have generated substantial interest in this peptide as a
potential treatment for obesity.86
A number of other gut and pancreatic peptides released
postprandially, which may have specific effects on inhi-
bition of food intake, include gastric inhibitory peptide
(GIP), amylin, enterostatin and ApoA-IV. Oxyntomodulin
(OXM) is another product of preproglucagon post-
translational processing and it has very similar anorectic
effects as GLP-1 in both rodents and humans.87,88
Intravenous infusion of OXM has been noted to reduce
plasma ghrelin concentrations in humans.89 Further work
is required to determine the precise role of OXM in
human appetite regulation and its potential as a treatment
option for obesity.
Ghrelin is another gut-derived hormone that has gener-
ated a substantial level of interest recently. This peptide is
synthesized in the stomach and is the endogenous ligand
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251
for the previously identified orphan receptor, growth
hormone secretagogue receptor (GHS-R), so called because
activation of GHS-R in the hypothalamus resulted in pitu-
itary growth hormone release.90 Ghrelin contrasts with
other gut hormones in that its primary action involves
stimulation of food intake, and indeed, chronic adminis-
tration in rodents leads to obesity.91 It is also a potent stimu-
lator of food ingestion in humans on peripheral
administration.92 Ghrelin concentrations are higher during
fasting state and concentrations rise further just before spon-
taneous feeding, strongly suggesting a role in meal
initiation.93 Plasma concentrations of ghrelin are low in
obesity and interestingly a fall in ghrelin concentrations
after gastric bypass surgery, with an associated loss of
pre-meal peak, has been posited as a factor contributing to
the suppression of appetite observed with this
procedure.87,94
Integrated mechanisms regulating
energy intake
With the recent advances in our understanding of the
complex pathways involved in regulating appetite, satiety
and body nutrient stores, an integrated model of these pro-
cesses can be constructed (Figure 3). In essence, it would
appear that the short-term regulation of food intake is deter-
mined, in part, by both neural and endocrine meal initiation
and meal termination signals from the gastrointestinal tract.
In addition, circulating concentrations of blood metabolites,
e.g. glucose, amino acids and fatty acids, also contribute to
these regulatory mechanisms. In relation to long-term body
‘energy stores’, lipostatic signals such as leptin and insulin
mediate between the peripheral adipose tissue and the
central neuroendocrine pathways in the hypothalamus
and beyond to maintain energy homeostasis. This rep-
resents a simplistic model and undoubtedly, in the
complex energy homeostatic milieu, gut-derived appetite
regulating hormones and the ‘lipostatic’ hormones have
Gut
CCK, GLP-1,
PYY (3-36)
Ghrelin etc.
Short-term regulatory signals
Energy
intake
Higher CNS
Hypothalamus
centres
Energy
expenditure Long-term regulatory signals
Leptin
Insulin
Adipose tissue
Figure 3 Integrated model of short- and long-term energy intake control
CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; PYY3-36, peptide
YY3-36; CNS, central nervous system
252 Annals of Clinical Biochemistry Volume 45 May 2008
................................................................................................................................................
effects across the spectrum of both short- and long-term
energy balance. Moreover, there is no doubt that higher
brain centres controlling complex behaviour patterns
provide a major input into both short- and long-term path-
ways, modulating these responses.
Management of obesity
Clinical approach to the obese patient
While the major objectives of public health strategies are
aimed at prevention of obesity, it is critically important
that detection and management of established obesity and
the associated co-morbidities are emphasized in current
clinical practice.6,7,19,95,96 The problem of obesity has
reached such a level that health-care institutions in the UK
and Ireland are now recognizing the need for specialized
obesity clinics to tackle many of these issues. In fact, any
effective clinical strategy will require a multidisciplinary
approach with input from medical staff, including general
practitioners and hospital-based specialists, dieticians, clini-
cal psychologists and physiotherapists among others.96
In relation to the medical approach to obese subjects,
a clear medical history including assessment of co-
morbidities, e.g. diabetes, CVD and operative history,
should be ascertained. In view of the fact that many
common drugs, e.g. antidepressants, insulin, beta-blockers,
corticosteroids, anticonvulsants and the oral contraceptive
pill, can cause or exacerbate weight gain, a lucid medication
history is also important. The overall weight and dieting
history is essential as is an assessment of physical activity.
Obesity is often familial, either as a result of shared environ-
ment, genetics or the combinations of these two factors. In
addition, many obese subjects suffer with low self-esteem
and there may be clear psychological issues to be addressed
as either a cause of morbidity or a barrier to successful treat-
ment. In female patients, issues relating to fertility should be
broached.
Any examination in the context of obesity must include a
minimum set of anthropometric measures of obesity,
including BMI, WC and blood pressure. Baseline investi-
gations should encompass a biochemical profile, with
‘renal profile’, ‘liver profile’, ‘thyroid function tests’, as
well as fasting lipid profile and glucose. In suspected
Cushing’s syndrome appropriate plasma and urine screen-
ing investigations should be performed. In female patients
with features suggestive of polycystic ovarian syndrome
(PCOS), concentrations of gondotrophins, relevant sex hor-
mones and sex hormone-binding globulin (SHBG) should
be measured. Of note, low concentrations of SHBG are
encountered in PCOS, but suppression of SHBG is also a
feature in male subjects with morbid obesity. In addition,
both total and free testosterone concentrations are low,
although gonadotrophins are usually normal, indicating
that obesity-related biochemical hypogonadism is most
probably clinically insignificant.97 Of course, caution needs
to be exercised in interpreting such data in the presence of
hypothalamic or pituitary pathology.
The presence of co-morbidities or aberrant results of base-
line tests may precipitate further investigations such as an
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oral glucose tolerance test (OGTT), haemoglobin A1c
(HbA1c), echocardiogram or exercise stress test, radiological
imaging. While obesity may be associated with normal
fasting glucose concentrations or an OGTT, underlying
insulin resistance may still be present. Thus, measurement
of indices such as fasting glucose to insulin (G/I) ratio
may have a role to play in documenting the degree of
insulin resistance, particularly in paediatric obesity and
PCOS. Caveats relating to cross-reactivity with proinsulin
and the absence of standardized insulin assays indicate
that caution should be exercised in the interpretation of
the G/I ratio, particularly between laboratories.
Elements within the clinical history and examination such
as severe early-onset hyperphagia or obesity, a strong
family history of obesity, associated developmental delay
and the presence of dysmorphic features should suggest
the possible need for molecular genetic and cytogenetic
analysis. In children with a suggestive history, and in
whom obesity is the predominant or only disorder,
measurement of serum leptin and plasma insulin and proin-
sulin may give insight into the presence of congenital leptin
or PC1-deficient states, respectively.98 It should be noted
however that contrary to what was initially reported, mark-
edly elevated concentrations of serum leptin are not a
feature of inherited LEPR deficiency.59 Detection of
MC4R-deficient state is primarily dependent on mutation
scanning of the MC4R gene.98
Treatment options in obesity
In planning treatment programmes for obesity, it is import-
ant to bear some fundamental issues in mind. Obesity is a
chronic problem and therefore will most likely require life-
long management, as maintenance of weight loss can be
very difficult to sustain. Any treatment targets should be
realistic and agreed with the patient concerned. Moreover,
different patients may require different approaches, as no
single treatment is effective in everyone. In terms of
outcome, a 10% reduction in baseline weight is likely to sub-
stantially benefit patients in terms of metabolic morbidity.
The cornerstone of all obesity treatment programmes is
lifestyle modification with specific emphasis on diet and
physical activity levels.6,7,95,96 Dietary restrictions can
range from the more traditional low or very low calorie
diets through to high-protein – low-carbohydrate diets,
such as the Atkins diets or the low-glycaemic index (GI)
diets, both of which are currently receiving a high media
profile, although medical opinion on their value remains
to be defined. Exercise and dietary regimens may be com-
bined with specific behavioural therapy measures.
Pharmacotherapeutic intervention is usually considered if
a 5% reduction in weight is not attained within a minimum
of three months of lifestyle modification.96,99 While many
drugs may have an anti-obesity action, currently National
Insitute for Health and Clinical Excellence (NICE) guide-
lines recommend the use of either orlistat or sibutramine
in the treatment of obesity in the UK. Orlistat is an intestinal
lipase inhibitor and effectively induces a partial state of fat
malabsorption, with 33% of dietary fat remaining unab-
sorbed. It is unsurprising, therefore, that the principal
 Crowley. Overview of human obesity and central mechanisms 253
................................................................................................................................................

side-effects of this medication relate to GI disturbances, Obesity epidemic: implications for

including bloating, flatulence, diarrhoea and abdominal clinical biochemistry
pain.96,99 Sibutramine acts in the CNS and inhibits re-uptake
The spiralling increase in the prevalence of obesity and
of both serotonin and noradrenaline. Thus, its effects
allied health problems such as, T2DM and CVD, has led
include an anorectic effect through activation of 5-HT recep-
to the realization that the management of obesity is now
tors, including 5-HT2c, and a- and b-adrenergic receptors
an intrinsic component of mainstream medical practice.
within the CNS. It may also promote thermogenesis,
However, despite the huge number of patients afflicted
although this probably plays a minor role in its
with this condition there is still a long way to go in terms
weight-reducing action. Sibutramine has a moderate side-
of providing a comprehensive clinical service dedicated to
effect profile with problems such as dry mouth, headache,
managing obesity in many hospitals. Obesity is fundamen-
insomnia and constipation being encountered. One particu-
tally a metabolic disorder and as such chemical pathologists
lar issue relates to a possible increase in both systolic and
and metabolic physicians are well situated to address this
diastolic blood pressure, thus requiring careful follow-up
service deficit. Indeed, exposure to the management of
in treated patients. Both orlistat and sibutramine are
obesity and its co-morbidities should be a core aspect of
reported to induce a 5 – 10% weight loss from baseline,
training in metabolic medicine and chemical pathology.
and are particularly effective if combined with adequate
Clearly, the provision of a substantive clinical obesity
lifestyle measures. These agents are recommended for use
service requires a comprehensive clinical biochemistry lab-
in patients with BMI . 30 kg/m2 or BMI . 27 kg/m2 in
oratory. In particular, the investigation of the causes of
the presence of co-morbidities and should be used under
obesity requires a repertoire of general biochemistry and
close medical supervision.96,99
endocrine tests. Of course, this also has implications for
In recent years, evidence has emerged implicating the
workload within such laboratories in view of the high preva-
endocannabinoids, anandamide and 2-arachidonoyl gly-
lence and continuing epidemiological trends of obesity.
cerol, and their associated receptor CB1 in the regulation
The elucidation of the molecular mechanisms underlying
of food intake. More specifically, it has been noted that
appetite control and satiety brings with it the prospect of
CB1 receptor gene (Cnr 1) knockout mice eat less than wild-
developing new diagnostic assays for use in the investi-
type littermates. In addition, defective leptin signalling on
gation of obese patients. Even at this stage one could
ob/ob and db/db mice is associated with elevated hypothala-
cogently argue that the measurement of plasma leptin
mic concentrations of endocannabinoids. This has inevitably
should be available in centres with specialist obesity
led to the development of selective CB1 anatagonists by a
clinics, particularly involving paediatric practice. Similar
number of pharmaceutical companies. Rimonabant is cur-
arguments could be made in favour of ghrelin and
rently the only CB1 receptor with European agency for the
PYY3-36. Moreover, the prevalence of MC4R mutations in
Evaluation of Medicinal Products (EMEA) approval for
childhood-onset severe obesity is such that the inclusion
clinical use.99 Based on double-blind placebo-controlled ran-
of MC4R molecular diagnostics in regional biochemical gen-
domized multicentre trials, i.e. rimonabant in obesity
etics laboratories is worth considering. As should be the
(RIO)-North America, RIO-Europe, RIO-Lipids and
case for any specialized laboratory test, protocols for use
RIO-Diabetes, it would appear that a dose of 20 mg of rimo-
and interpretation of such tests will require substantial
nabant, in combination with a hypocaloric diet, can lead to
input from clinical biochemistry personnel.
significant (.5%) weight reduction.100 – 102 Moreover,
Another factor to consider is the role of clinical biochemis-
observed improvements in HBA1c, dyslipidaemia and
try laboratory in both proactively promoting research into the
inflammatory markers suggest that rimonabant may
realm of obesity and facilitating such research. Certainly,
address not only obesity per se, but also major
there are already a number of major clinical biochemistry lab-
co-morbidities, and thus could lead to a reduction in the
oratories in the UK involved in internationally recognized
number of medications needed to treat obesity and its
research in this area and this may expand in the future.
associated cardiometabolic risk.102 Adverse effects have
been reported including nausea, dizziness, diarrhoea and
insomnia. Psychiatric disorders, mainly depression, were Conclusions
reported in 6 –7% of rimonabant-treated individuals, war- Obesity is a major public health issue. Understanding the
ranting discontinuation.99 Therefore, this class of drug physiological and molecular mechanisms regulating
needs to be used with caution in the presence of significant energy balance will inform the development of effective pre-
psychiatric morbidity and may well be contraindicated. vention, diagnostic and treatment strategies for this con-
However, further studies are ongoing to determine the dition, and over the last decade enormous progress has
exact extent of its use in clinical practice and, of note, the been made in this field. Undoubtedly, clinical biochemistry
Food and Drug Administration has held back approval in has a role to play in facilitating such initiatives.
the USA pending the outcome of these studies.
Surgical treatments of obesity are usually reserved for ACKNOWLEDGEMENTS
morbid obesity (BMI . 40 kg/m2). Various bariatric pro-
cedures are used in practice, including laparoscopic gastric Many thanks to Professor John Nolan, Dr Sadaf Farooqi,
banding and gastric bypass. Surgical treatment can be Dr Giles Yeo, and Professor Steve O’Rahilly, with whom
very effective and may substantially reduce mortality discussion of various issues covered in this manuscript
associated with morbid obesity.96 was very helpful in its preparation.

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254 Annals of Clinical Biochemistry Volume 45 May 2008
................................................................................................................................................
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