a practical guide for clinicians - scion medicalmanaging obesity prelims.indd 2 07/11/2018 15:18 a...

The pandemic of obesity in the majority of countries of the world has become a major health problem: obesity leads to a number of serious diseases including type 2 diabetes, cardiovascular disease, hypertension, stroke, cancer, psychological problems and a poor quality of life. Obesity affects almost every branch of medicine and clinical practice and this puts a huge strain on healthcare provision. Managing Obesity has been written specifically for non-specialists (GPs, junior doctors and medical students) who increasingly need to treat obese patients. The book begins with an overview of the causes of obesity, the mechanisms that lead to individuals becoming obese and the health issues associated with being obese. Later chapters discuss how obesity can be managed, including advanced pharmacotherapy options and surgery.

SAFFRON WHITEHEAD & GUL BANO

A practical guide for cliniciansOBESITY

MANAGING

9 781911 510178

ISBN 978-1-911510-17-8

www.scionpublishing.com

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A practical guide for clinicians

OTHER TITLES FROM SCION

OBESITYMANAGING


MANAGING

Managing Obesity Prelims.indd 1 07/11/2018 15:18F01-MangingObesity-Prelims.indd 1 14/12/2018 14:06

Managing Obesity Prelims.indd 2 07/11/2018 15:18


MANAGING

Saffron WhiteheadEmeritus Professor of Endocrine Physiology

St George’s, University of London

and

Gul BanoSenior Lecturer in Endocrinology and Diabetes

St George’s University Hospitals NHS Foundation Trust, London


Cover design by Andrew Magee Design LtdCover photos reproduced under licence from stock.adobe.comLine artwork by Hilary Strickland Illustration, Bath, UKTypeset by Evolution Design & Digital Ltd (Kent)Printed in the UK

Last digit is the print number: 10 9 8 7 6 5 4 3 2 1

© Scion Publishing Limited, 2019

ISBN 9781911510178

First published 2019

All rights reserved. No part of this book may be reproduced or transmitted, in any form or by any means, without permission.

A CIP catalogue record for this book is available from the British Library.

Scion Publishing Limited

The Old Hayloft, Vantage Business Park, Bloxham Road, Banbury OX16 9UX, UK www.scionpublishing.com

Important Note from the Publisher

The information contained within this book was obtained by Scion Publishing Ltd from sources believed by us to be reliable. However, while every effort has been made to ensure its accuracy, no responsibility for loss or injury whatsoever occasioned to any person acting or refraining from action as a result of information contained herein can be accepted by the authors or publishers.

Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be pleased to acknowledge in subsequent reprints or editions any omissions brought to our attention.

Registered names, trademarks, etc. used in this book, even when not marked as such, are not to be considered unprotected by law.


Preface ..............................................................................................................................vii

Acknowledgements ..............................................................................................viii

Abbreviations .............................................................................................................. ix

1 Fat’s the issue ................................................................................................................1

2 Basics of digestion, absorption and metabolism...........................15

3 What makes us eat and how do we control it? ................................ 29

4 Disorders of metabolism .................................................................................. 43

5 Diets and exercise .................................................................................................. 59

6 Genetics of obesity ................................................................................................ 83

7 Childhood obesity .................................................................................................. 93

8 Secondary obesity ...............................................................................................105

9 Medical management of obesity ............................................................. 115

10 Bariatric surgery ....................................................................................................129

Index ...............................................................................................................................143

Contents

v

Cover design by Andrew Magee Design LtdCover photos reproduced under licence from stock.adobe.comLine artwork by Hilary Strickland Illustration, Bath, UKTypeset by Evolution Design & Digital Ltd (Kent)Printed in the UK

Last digit is the print number: 10 9 8 7 6 5 4 3 2 1

© Scion Publishing Limited, 2019

ISBN 9781911510178

First published 2019

All rights reserved. No part of this book may be reproduced or transmitted, in any form or by any means, without permission.

A CIP catalogue record for this book is available from the British Library.

Scion Publishing Limited

The Old Hayloft, Vantage Business Park, Bloxham Road, Banbury OX16 9UX, UK www.scionpublishing.com

Important Note from the Publisher

The information contained within this book was obtained by Scion Publishing Ltd from sources believed by us to be reliable. However, while every effort has been made to ensure its accuracy, no responsibility for loss or injury whatsoever occasioned to any person acting or refraining from action as a result of information contained herein can be accepted by the authors or publishers.

Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be pleased to acknowledge in subsequent reprints or editions any omissions brought to our attention.

Registered names, trademarks, etc. used in this book, even when not marked as such, are not to be considered unprotected by law.


F01-MangingObesity-Prelims.indd 6 14/12/2018 14:06

The pandemic of obesity in the majority of countries of the world has become a major health problem and it is predicted that the prevalence of obesity will continue to increase worldwide into the foreseeable future. Obesity leads to a number of serious diseases including type 2 diabetes, cardiovascular disease, hypertension, stroke, cancer, psychological problems and a poor quality of life. As a consequence longevity is reduced whilst the cost of treating these co-morbidities escalates.

Unravelling the complexities of obesity and advancing our understanding of metabolic syndrome in relation to excess visceral fat has become a large focus of research. Different aspects of this research include mechanisms that regulate appetite and food intake, nutrient absorption and utilisation, metabolism and energy expenditure as well as disturbances in the function of excess fat itself – ‘sick fat’ or adiposopathy. These avenues of research have led to potential new targets for drug development in the treatment of obesity.

Currently there is no magic pill to cure obesity and many medications have unwanted or serious side-effects with only modest reduction in weight. The first-line treatment of obesity is still through diet, exercise and lifestyle changes to increase general physical activity, but compliance and maintenance are frequently problematic. Medical management of obesity can be a useful adjunct but as a last resort, bariatric surgery may be the best option in people who are morbidly obese or severely obese with co-morbidities and who fail to respond to other forms of treatment.

There are literally hundreds of books on obesity ranging from long, multi-author textbooks to those for the lay reader, as well as endless books and websites on weight-reducing diets. Today the prevalence of obesity can affect every branch of medicine and clinical practice and this short book has been written for GPs, junior doctors and medical students to give an overview of the problems associated with obesity and metabolic syndrome. The epidemiology, investigation, causes and treatment of obesity are outlined and are underpinned by the pathophysiological changes that occur with excess fat causing serious disease. We hope that it will provide a succinct and clear understanding of this growing medical pandemic.

Saffron WhiteheadGul Bano

Preface

vii


Acknowledgements

The authors would like to express our sincere and special thanks to Scott Lonnee and Joanna Lam, dietitians to obesity services at St George’s Hospital, for their valuable contributions to Chapter 5 on diet and lifestyle changes for managing obesity.

We would also like to thank Jenny Abraham and Hassan Kahal, both at University Hospitals of Coventry and Warwickshire (UHCW) NHS Trust, for reading the manuscript and providing helpful feedback.

viii


Abbreviations

ACE angiotensin-converting enzyme

ACTH adrenocorticotrophic hormone

ARB angiotensin receptor blocker

BBS Bardet–Biedl syndrome

BDNF brain-derived neurotrophic factor

BED binge eating disorder

BMI body mass index

BMR basal metabolic rate

BPD biliopancreatic diversion

CBT cognitive behavioural therapy

CCK cholecystokinin

CDI C. difficile infection

CHO carbohydrates

CRH corticotrophin-releasing hormone

CRP C-reactive protein

CS Cushing syndrome

CT computerised tomography

CVD cardiovascular disease

DNP 2,4-dinitrophenol

DPP dipeptidyl peptidase

DXA dual energy X-ray absorptiometry

ECG electrocardiogram

EEC enteroendocrine cell

ER extended release

EWL excess weight loss

FDA Food and Drug Administration

ix


FMT faecal microbiota transplant

FPG fasting plasma glucose

GH growth hormone

GI gastrointestinal

GIP gastric inhibitory peptide / glucose-dependent insulinotrophic polypeptide

GLP-1 glucagon-like peptide-1

GWAS genome-wide association studies

HbA1c glycated haemoglobin

HCC hepatocellular carcinoma

HCP health care professional

HDL high-density lipoproteins

HDL-C HDL cholesterol

HR heart rate

IFG impaired fasting glucose

IGF insulin-like growth factor

IGT impaired glucose tolerance

LADA latent autoimmune diabetes

LCD low-calorie diet

LDL low-density lipoproteins

LDL-C LDL cholesterol

LPS lipopolysaccharides

metS metabolic syndrome

MRI magnetic resonance imaging

MSH melanocyte-stimulating hormone

MUFA monounsaturated fatty acids

NAFLD non-alcoholic fatty liver disease

NASH non-alcoholic steatohepatitis

OSA obstructive sleep apnoea

OXM oxyntomodulin

PCOS polycystic ovary syndrome

POMC pro-opiomelanocortin

PP pancreatic polypeptide

PUFA polyunsaturated fatty acids

PWS Prader–Willi syndrome

PYY peptide tyrosine tyrosine

RMR resting metabolic rate

Abbreviations

x


RTS Rubinstein–Taybi syndrome

RYGB Roux-en-Y gastric bypass

SCFA short chain fatty acid

SGLT2 sodium-glucose co-transporter-2

SNAC N-[8-(2-hydroxy benzoyl)amino] caprylate

T2DM type 2 diabetes mellitus

TAGs triacylglycerol / triacylglyceride

TBW total body weight

TCA tri-carboxy acid

TSH thyroid-stimulating hormone

TZD thiazolidinedione

VLCD very low-calorie diet

VLDL very low-density lipoproteins

WAGR Wilms tumour, aniridia, genitourinary anomalies and retardation

WHO World Health Organization

Abbreviations

xi


8.1 Introduction ..............................................................................................................106

8.2 Hypothalamic disorders ..................................................................................106

8.3 Endocrine disorders associated with obesity ................................108

8.4 Antipsychotic drugs and obesity ............................................................. 113

8.5 Summary ..................................................................................................................... 114

Further reading ...................................................................................................... 114

Chapter 8

Secondary obesity

105

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Chapter 8 : Secondary obesity

8.1 IntroductionSecondary obesity defines obesity related to factors other than diet, lifestyle and genetics, as have been outlined in previous chapters. Several endocrine disorders are related to obesity, including hypothalamic disorders / damage, where appetite regulation is integrated (Chapter 3). The hypothalamus also controls hormone secretions from the pituitary gland which send signals to the peripheral endocrine glands. These include the thyroid gland, the adrenal cortex and gonads. Isolated dysfunction of these glands is also associated with obesity.

8.2 Hypothalamic disordersHypothalamic obesity can occur in response to any hypothalamic damage and is commonly observed in patients with pituitary tumours and suprasellar extension, particularly craniopharyngioma (50%), hypothalamic tumours, trauma and inflammation, or after pituitary surgery or radiotherapy. The hypothalamus not only integrates appetite-regulating signals but is also important in autonomic functions and thermoregulation. Thus, any damage to the hypothalamus can have variable effects.

The mechanism of hypothalamic obesity varies between patients, depending upon the extent of hypothalamic damage and involvement by pituitary tumours.

The causes of weight gain are: • hyperphagia due to structural damage of the hypothalamic control of food intake • autonomic dysfunction which increases vagal tone, leading to hyperinsulinaemia

and a low RMR • impaired energy expenditure and thermoregulation • associated endocrinopathy such as growth hormone (GH) deficiency,

hypothyroidism, precocious or delayed puberty, ACTH deficiency and diabetes insipidus

• reduced physical activity due to prolonged periods of medical treatment.

The treatment of hypothalamic obesity is via a multidisciplinary approach. The hypothalamus is very sensitive to both surgical intervention and external beam radiation. Newer ways to treat tumours employ a more conservative approach using stereotactic biopsy and conformal irradiation rather than total resection as a primary therapy. Hormone replacement, especially GH, is of vital importance in the treatment of hypothalamic obesity. Patients at high risk of hypothalamic obesity should be identified and counselled regarding lifestyle and therapeutic changes to prevent weight gain, together with specific hormone replacement as indicated. Recent advances in treatment such as bariatric / metabolic surgery (gastric band / sleeve / bypass; see Chapter 10) offer an alternative to the treatment of hypothalamic obesity.


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8.2 Hypothalamic disorders

Case 8.1

A 15-year-old boy presented with a 6-month history of headaches and vomiting. At the initial assessment he had visual failure and papilloedema (optic disc swelling). A magnetic resonance imaging (MRI) scan showed a suprasellar cystic lesion breaching the floor of the third ventricle with hydrocephalus suggestive of a craniopharyngioma*. Preoperative endocrine review elicited a history of tiredness, but no problems with growth. He was drinking more than usual and frequently passing a large volume of urine. On examination, his height was 168 cm and weight 52 kg (see Figure 7.1). He was prepubertal. Baseline investigation showed that the prolactin level was normal and a-fetoprotein and β-human chorionic gonadotrophin levels were undetectable. Thyroid function tests were indicative of central hypothyroidism (thyroid-stimulating hormone 0.01 mIU/L; free T4 7 pmol/L). Initial endocrine management included thyroxine and hydrocortisone replacement and further endocrine tests revealed him to have panhypopituitarism.

He had insertion of an external ventricular drain followed by radical resection. Histology confirmed the diagnosis of craniopharyngioma and neurosurgery was followed by a 6-week course of external beam radiotherapy as there was postoperative evidence of residual tumour.

Following surgery, he developed diabetes insipidus and this was treated with desmopressin. After his treatment for craniopharyngioma, he was noted to be hungry all the time and eating a lot. During the first postoperative year, his weight increased from 52 kg to 98 kg. He was feeling depressed and his excessive weight was beginning to cause mobility problems. His weight increased further to 120 kg. Testosterone and GH replacement were started. Over a period of 6 months, his weight reduced to 104 kg. He could not, however, control his hunger and his weight again increased to 126 kg. He was offered bariatric surgery and had a gastric bypass. Six months after the surgery, he weighed 102 kg and after 12 months he now weighs 94 kg. He remains on hormone replacement and has multivitamins.

*A craniopharyngioma is a tumour which generally occurs above the pituitary gland and represents 5–10% of childhood brain tumours, with about 30 new cases a year in children in the UK. Prior to surgery the boy was not overweight, being in the 30–40 percentile range of the median BMI for children (Box 7.1). His weight gain was caused by damage to the hypothalamus.


108


8.3 Endocrine disorders associated with obesityHormones alter metabolism and thus it is not surprising that several endocrine disorders are associated with obesity (Figure 8.1). These include: • PCOS • Cushing syndrome • hypothyroidism • GH deficiency • hypogonadism.

Hypothalamic obesity

Cushing syndrome

GH de�ciency

Hypogonadism

PCOS

Hypothyroidism

Obesity

Figure 8.1 Major endocrine disorders associated with obesity.

8.3.1 Polycystic ovary syndromePolycystic ovary syndrome (PCOS) is the most common hormonal abnormality in women of reproductive age, affecting approximately 7% of this population. Obesity is a common finding associated with PCOS and indeed 40–80% of women with PCOS are reported to be overweight or obese. PCOS has reproductive and metabolic manifestations and obesity aggravates many of its reproductive and metabolic features. The hormonal manifestations of PCOS include increased androgen production, menstrual irregularity, hirsutism and infertility. The metabolic features are defects in insulin action and β-cell function, increasing the risk for glucose intolerance and T2DM, and NAFLD (Section 4.8). Familial aggregation of PCOS supports a genetic susceptibility to this disorder but the prevalence of PCOS is markedly increased in overweight and obese women. Overall, reproductive disturbances are common in obese women even in the absence of PCOS. The risk of anovulatory infertility increases at a BMI of 24 kg/m2 and continues to rise with increasing BMI.

Several endocrine imbalances are associated with obesity and PCOS, including ghrelin, androgens and oestrogens. The levels of ghrelin, an orexigenic peptide secreted by the stomach (Section 3.2.2), increase sharply before meals, leading to hunger, and drop after feeding, leading to satiety. Obese individuals and women with PCOS have low ghrelin levels that fail to suppress following food intake. This reduces satiety and leads to weight gain. Hyperandrogenaemia, a common indicator of PCOS, may also contribute to the development of visceral adiposity in PCOS.


109

8.3 Endocrine disorders associated with obesity

8.3.2 Oestrogens and obesityOestrogens play a role in obesity, affecting body fat distribution and metabolism. In premenopausal women most oestrogens come from the ovaries, but adipose tissue can convert androgens (mainly derived from the adrenal cortex) to oestrogens. Adipose tissue is also a source of oestrogens in postmenopausal women and in obesity, oestrogen levels are elevated due to increased fat mass. Oestrogens are considered to be responsible for fat distribution, favouring deposition around the hips (pear-shaped) and decreasing visceral fat (apple-shaped) (Figure 8.2). In hypo-oestrogenic states, such as the menopause, the deposition of visceral fat is increased, raising the probability of developing metabolic syndrome (Chapter 4) and its associated risks such as insulin resistance, cardiovascular disease, hypertension, dyslipidaemia and cancer (Chapter 1). Hormone replacement therapy can prevent the increased visceral fat deposition and interestingly, oestrogen treatment to male–female transgenders increases subcutaneous fat while having little effect on visceral adipose tissue. Regarding metabolism, oestrogens increase insulin sensitivity by acting on the liver, skeletal muscle and adipose tissue. They also act on the neural circuits controlling food intake and energy expenditure in the hypothalamus. Thus, changes occur in these processes in hypo-oestrogenic conditions.

Figure 8.2 Excess visceral (apple-shaped) and excess subcutaneous (pear-shaped) fat depositions.Visceral fat deposits have greater metabolic effects than subcutaneous fat (Chapter 4).

8.3.3 The hypothalamic–pituitary–adrenal axis and obesityObesity is a clinical feature of Cushing syndrome (CS) and is characterised by the central distribution of adipose tissues. CS is caused by prolonged exposure to glucocorticoid excess. The glucocorticoid can be derived from four potential sources: • exogenous glucocorticoids, including oral, topical or inhaled steroid • pituitary tumours (Cushing disease) • adrenal tumours • ectopic adrenocorticotrophic hormone (ACTH) secretion.


110


Case 8.2

A 21-year-old lady was referred to the Endocrine Clinic from a peripheral hospital. She was well until February 2015, when she started feeling extremely tired and had rapid weight gain. In one year she went from to 82 kg to 114 kg. She also started developing stretch marks on her stomach and noticed easy bruising. She used to work in a cinema, but stopped working because she could not walk up the stairs. Her periods became irregular. Her last menstrual period was 6 months ago. She had also noticed acne and hirsutism. Her weight gain was continuous and she had to use a mobility aid for walking. Her vision was normal but she had become forgetful and had low mood. In her past medical history, she had a history of fibromyalgia and hypermobile joints. She was taking gabapentin (an anti-epileptic drug) and vitamin D. She did not smoke and did not drink alcohol. She had no history of endocrine pathology in her family. She subsequently developed back pain and was found to have a compression fracture of the lumbar spine.

When examined at the endocrine clinic her weight was 120.8 kg with a height of 159 cm, giving her a BMI of 47.8 kg/m2. She had purple striae on her abdomen and upper thighs. Her blood pressure was 150/96 mmHg. Laboratory testing showed elevated 24-hour urine-free cortisol values of 270 and 300 mol/24 hr (NR 60–120). She had a low-dose dexamethasone suppression test with corticotrophin-releasing hormone (CRH) stimulation. Her cortisol failed to suppress to <50 nmol/L after 0.5 mg of dexamethasone 6-hourly for 48 hours. Both her ACTH and cortisol increased after CRH stimulation, indicating ACTH-dependent Cushing disease. Her MRI scans clearly showed a 7 × 5 mm microadenoma on the left side of her pituitary that reached the medial wall of the left cavernous sinus but did not show evidence of invasion. Inferior petrosal sinus sampling was performed, which showed that the pituitary was the source of her Cushing’s and lateralisation was to the left side.

This patient with confirmed Cushing disease underwent transsphenoidal resection of her pituitary microadenoma. After surgery, the patient developed transient diabetes insipidus that settled in 48 hours. On day 1 postoperative, her cortisol was 50 nmol/L. She had two further cortisol levels of <50 nmol/L, indicating successful surgery. She was replaced with hydrocortisone and discharged. Her histology confirmed ACTH-producing adenoma. She remains well and is losing weight. Her current weight is 90 kg and her periods have restarted. She has normal blood pressure and her acne and hirsutism have also improved.

Cortisol synthesis and secretion from the adrenal cortex is controlled by CRH from the hypothalamus and ACTH from the pituitary gland. Cortisol is a metabolic hormone that increases blood glucose concentrations by increasing gluconeogenesis from amino acids released by muscle, and has mild effects on the breakdown of lipids. It has many other actions including actions on the brain, cardiovascular system, immune system, kidneys, skin, connective tissue, bone and the foetus. The metabolic dysfunctions that occur in Cushing syndrome are shown in Figure 8.3.


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8.3 Endocrine disorders associated with obesity

Overall the metabolic manifestations of excess glucocorticoids (hypercortisolism) are: • increased gluconeogenesis and insulin resistance, with overt diabetes diagnosed in

20–47% of patients and impaired glucose tolerance in 21–64% of cases of CS • redistribution of body fat, increasing central adiposity (apple-shape) and resulting

in changes of adipokine secretions and increasing food intake • stimulation of lipolysis which contributes to dyslipidaemia; this includes raised

cholesterol and increased TAGs and is observed in 37–71% of patients • inhibition of the GH and insulin-like growth factor (IGF) axis which may be associated

with Cushing syndrome; replacement may be required, particularly in children.

All of these metabolic changes can predispose a patient to obesity, cardiovascular risks and other co-morbidities.

8.3.4 Obesity and thyroid diseaseThyroid hormones are responsible for approximately 30% of the resting metabolic rate (RMR) and thus play an important role in the fine tuning of energy intake and energy expenditure. Thyroid hormones regulate: • basal metabolism • thermogenesis • food intake • fat oxidation.

They also have a role in lipid and glucose metabolism.

Excess glucocorticoids

Liver

Gluconeogenesis

Lipogenesis

Insulin sensitivity

Adipose tissue

Adipogenesis

Lipolysis

Free fatty acids

Insulin sensitivity

Altered adipokine secretions

Hypothalamus

Appetite

Muscle

Proteolysis

Glycogen synthesis

Insulin sensitivity

Glucose uptake

Dyslipidaemia Hyperglycaemia Proximal myopathy Central obesity CVD GH/IGF axis

Figure 8.3 Metabolic consequences of Cushing syndrome.CVD, cardiovascular disease; GH, growth hormone; IGF, insulin-like growth factor.


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Low levels of thyroid hormones in overt hypothyroidism correlate with a higher BMI and a higher prevalence of obesity, mainly caused by a reduction in RMR. In humans, hypothyroidism is associated with variable degrees of weight gain and is reported in about 50% of patients who present with obesity in primary care. Thyroxine replacement for hypothyroidism results in only a limited and modest weight loss. A quarter of obese patients are found to have subclinical hypothyroidism where thyroid-stimulating hormone (TSH) levels are typically at the upper limit of the normal range or are slightly increased, with low levels of free T4 (fT4) and a moderate increase in T3 or free T3 (fT3) levels. There is little benefit of thyroxine treatment in subclinical hypothyroidism to weight loss.

In the past thyroxine treatment to increase RMR has been used as a weight-reducing tool, but the problem is that when the excess thyroid hormone is stopped, weight is usually regained. Thus thyroxine should only be used to control body weight in obese patients with overt hypothyroidism.

8.3.5 Growth hormone and obesityGrowth hormone secreted by the pituitary gland has marked metabolic effects, as does cortisol, apart from stimulating growth.

The metabolic actions of GH are: • stimulation of glucose uptake into muscle and liver • increased protein accretion (anabolic) • inhibition of fat accumulation (lipolytic).

GH stimulates protein synthesis, increasing muscle and bone mass, and stimulates adipocyte lipolysis. Both excess GH hormone (i.e. acromegaly) and low GH levels induce insulin resistance, but the mechanism for these effects is not known.

Adult-onset growth hormone deficiency results in numerous clinical effects due to the metabolic actions of GH. These include: • increased visceral adipose tissue • increased insulin resistance • increased cardiovascular risk • decreased muscle mass • increase in body weight of 3.6–7.5 kg.

Thus there is a high prevalence of visceral adiposity, NAFLD and T2DM in GH-deficient patients, as seen in obese people. It is also associated with decreased muscle mass. Therapy with GH replacement is effective in restoring normal body fat distribution and stimulating adipocyte lipolysis.

Obesity is typically associated with low circulating GH concentrations compared to age-matched controls, while starvation has the opposite effect. The relationship between obesity and low GH hormone levels is not well understood but could involve the obesity-related hyperglycaemia which inhibits GH secretion, high circulating levels of free fatty acids and changes in adipokine secretions and other hormones.


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8.4 Antipsychotic drugs and obesity

8.3.6 Hypogonadism, sex hormones and obesityChanges in the level of both androgens and oestrogens are associated with obesity and play a role in the development of different phenotypes of obesity. The relationship between obesity and hypogonadism (loss of sex steroid secretions) is complicated, in that sex steroids can alter metabolism and distribution of fat – as occurs in puberty and the menopause – whilst obesity can alter the levels of steroids. The mechanism for the relationship between obesity and hypogonadism is not entirely clear but may involve impairment of the hypothalamic–pituitary axis, increased release of adipokines, leptin resistance and changes in steroid receptors and sex hormone-binding globulin. • In men: obesity is associated with low total testosterone levels and hypogonadism

and causes an increase in visceral adipose tissue and other metabolic dysfunctions. Since visceral fat mass and testosterone levels have an inverse relation, this could explain the increased visceral obesity with age in men.

• In women: obesity is associated with higher circulating concentrations of androgens, even in the absence of PCOS. It is well known that obesity is a risk factor for hypogonadism and inversely, hypogonadism may be a risk factor for obesity. The menopause is associated with increased central fat deposition, increased ratio of visceral to subcutaneous fat, reduced lean body mass and metabolic dysfunction.

Replacement therapy of testosterone (men) or oestrogen (women) can reduce visceral fat, although this is not an option for treating obesity. Interestingly, the increasing prevalence of obesity is linked with an increased proportion of patients seeking medical treatment for sexual dysfunction.

8.3.7 Causes or consequence of endocrine disorders related to obesity?Several endocrine disorders are associated with obesity. Whether many of these changes are an adaptive consequence of obesity, or whether they somehow contribute to or worsen the excessive weight accumulation, is not yet clearly known. The relationship appears bidirectional, and there are numerous causative and correlative factors on both sides of the equation. What is known is that hormones alter many aspects of metabolism, which can affect distribution of body fat, insulin resistance, the turnover of lipids and the resting metabolic rate. Thus, measuring hormone levels is an important part of investigating the causes of obesity.

8.4 Antipsychotic drugs and obesityIt is well recognised that second-generation antipsychotic drugs, such as clozapine, olanzapine, risperidone and quetiapine, are very successful in stabilising the symptoms of schizophrenia, which is estimated to affect 1% of the world population. A side-effect of these drugs, however, is that they stimulate food intake, leading to weight gain, hyperglycaemia due to insulin resistance, and lipid accumulation in adipose tissue and liver. The cause of hyperphagia and the metabolic changes that occur with these drugs


114


is not well understood, but some experimental evidence suggests that they interfere with neural signalling in the hypothalamus, which regulates appetite and food intake (Chapter 3), and may also interfere with a transcription factor which can alter lipid metabolism.

The interesting consequence of second-generation antipsychotic drug treatment is that the development of full-blown diabetes, obesity, and other metabolic consequences occurs more rapidly than does the development of obesity and metabolic changes in the general population, which can take up to 10 years. Unfortunately, no drug(s) to counteract this side-effect of antipsychotics have to date been developed.

8.5 SummarySecondary obesity refers to certain endocrine disorders that can cause weight gain. Whether this results in overt obesity or predisposes individuals to weight gain, leading to or exacerbating obesity, is not known. Conversely, obesity may lead to endocrine disorders. Any damage to the hypothalamus, e.g. tumours or trauma, affects not only the hypothalamic–pituitary axis in controlling endocrine secretions but also the hypothalamic integration of anorexigenic and orexigenic signalling from the periphery (Chapter 3), regulating food intake. Certain hormones alter metabolism, such as cortisol, thyroid hormones, growth hormone and sex steroids, which can increase weight gain.

Further readingCoyoy, A., Guerra-Araiza, C. and Camacho-Arroyo, I. (2016) Metabolism regulation by estrogens and their receptors in the central nervous system before and after menopause. Horm Metab Res, 48: 489–496.

Ferraù, F. and Korbonits, M. (2015) Metabolic comorbidities in Cushing’s syndrome. Eur J Endocrinol, 173: M133–157.

Karam, J.G. and McFarlane, S.I. (2007) Secondary causes of obesity. Therapy, 4: 641–650.

Naderpoor, N., Shorakae, S., Joham, A. et al. (2015) Obesity and polycystic ovary syndrome. Minerva Endocrinol., 40: 37–51.

Rojo, L.E., Gaspar, P.A., Silva, H. et al. (2015) Metabolic syndrome and obesity among users of second generation antipsychotics: a global challenge for modern psychopharmacology. Pharmacol Res., 101: 74–85.

Santini, F., Marzullo, P., Rotondi, M. et al. (2014) Mechanisms in endocrinology: the crosstalk between thyroid gland and adipose tissue: signal integration in health and disease. Eur J Endocrinol., 171: R137–152.

Sidhu, S., Parikh, T. and Burman, K.D. (updated 2017) Endocrine changes in obesity. In: De Groot L.J. et al. (eds) Endotext, www.endotext.org.


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