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C H A P T E R 1 1
Obesity and Multiple
Sclerosis
Katherine H. Saunders Mohini Aras Louis J. Aronne
Introduction
Obesity affects 39.8% of adults (93.3 million) and 18.5% of
children and adolescents (13.7 million) in the United States.
1
Obesity is defined as a body mass index (BMI) of greater than
or equal to 30 kg/m2 in adults and a BMI of greater than or
equal to age- and sex-specific 95th percentile of the 2000
Centers for Disease Control and Prevention growth charts in
children. 2 The medical costs associated with obesity are
tremendous. The latest published estimate was US$147 billion
in 2008.
3
Obesity is a multifactorial, chronic disease characterized by an
accumulation of visceral and subcutaneous fat, which leads to
a predisposition toward a wide variety of comorbid conditions.
4
Obesity-related comorbidities include many of the leading
causes of preventable death, such as heart disease, type 2
diabetes, stroke, and many types of cancer. Mechanisms
including abnormalities in lipid metabolism, insulin resistance,
inflammation, endothelial function, adipokine balance, and
inflammasome activation have been implicated in the
development of these weight-related chronic conditions,
including multiple sclerosis (MS) among patients with obesity.
4
Modest weight loss of 5% to 10% body weight is sufficient for
significant and clinically relevant improvements in risk factors
among patients with overweight and obesity.
5,6
This risk
reduction appears to be dose related, as a 10% to 15%
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reduction in body weight is associated with even greater odds
of clinically significant improvements in most risk factors. The
magnitude of weight loss at 1 year is strongly associated with
improvements in many parameters including blood sugar,
blood pressure, triglycerides, and HDL cholesterol.
Most patients have limited success with weight loss because of
the body’s resistance to the effects of lifestyle modifications.
Reduced caloric intake and increased energy expenditure are
counteracted by a variety of adaptive physiological responses.
7
Alterations in a range of hormones cause appetite to increase
and resting metabolic rate to slow out of proportion to what
would be expected based on changes in body composition.
8
This phenomenon, called metabolic adaptation or adaptive
thermogenesis, inhibits weight loss and leads to weight regain.
9,10
As a result, successful treatment of obesity requires a
multidisciplinary approach to counteract the body’s resistance
to weight loss. Although diet, physical activity, and behavioral
modifications are the cornerstones of weight management,
many patients require additional interventions, such as
antiobesity medications and/or bariatric surgery, to achieve
and maintain clinically significant weight loss.
In this chapter, we describe how obesity is a risk factor for
MS. We also review the available treatment strategies for
obesity, including medications and devices approved by the
US Food and Drug Administration (FDA), as well as bariatric
surgery. Finally, we examine the impact of obesity treatment
on MS and present a patient case that illustrates key points.
Obesity as a Risk Factor for Multiple
Sclerosis
Epidemiology
MS is a chronic autoimmune disease of the central nervous
system (CNS). It is an inflammatory and demyelinating
condition that affects both white and gray matter. Symptoms
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range from fatigue, numbness, and tingling to pain, blindness,
spasticity, incontinence, and paralysis. It is estimated that MS
affects between 400,000 to 1 million Americans and at least
2.3 million people worldwide.
11-13
MS affects twice as many
women as men. According to the World Health Organization,
rates of MS have increased over the last few years from
2.1 million in 2008 to 2.3 million in 2011. 12 The medical costs
associated with MS are significant and are estimated to be
upward of US$52,000 per patient per year.
11
MS is the second leading cause of neurological disease in
young people and leads to a wide range of functional
debilities. 12 The most common subtype is relapsing-remitting
MS, which is associated with numerous brain and spinal cord
lesions that resolve either partially or completely between
flares. 14 Pediatric MS, and clinically isolated syndrome, which
includes optic neuritis and transverse myelitis, are being
reported at increasing rates. 15 Although causes of MS remain
unknown, both genetic and environmental factors have been
implicated—human leukocyte antigen (HLA)-DRB1*15:01
allele, other non–major histocompatibility complex variants,
tobacco exposure, vitamin D deficiency, viral exposures,
reproductive history, and obesity.
11
The prevalence of obesity in MS is estimated to range from
21% to 37%. 16 The increasing prevalence of obesity over the
past few decades could account for increased rates of MS.
Numerous studies have confirmed an approximately twofold
increased risk of developing MS in women who were obese
during late adolescence/early adulthood (age 18-25 y) versus
women who had a BMI in the normal range during those
years.
17,18
This association between adolescent/early adult
obesity and MS has not been consistently shown in men.
There is also an association between childhood obesity and
MS. In 2013, a Danish prospective study of children in the
Copenhagen School Health Records Register found that girls
who were ≥95th percentile for BMI had a 1.61- to 1.95-fold
increased risk of MS compared with girls <85th percentile.
19
Among boys, this association was attenuated and only
significant in particular age groups (e.g., among boys aged 810 y). Given the strong association between childhood obesity
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and adult obesity, treating childhood obesity may be an
important initiative to reduce the prevalence of MS in
adulthood.
Pathophysiology
Genetics
The HLA-DRB*15:01 allele is the most common genetic
marker for the risk of developing MS. This allele carries a 2.9fold increased risk of developing MS among individuals with a
normal BMI. The presence of both obesity and the HLADRB1*15 allele confers a 9.1-fold increased risk of
developing MS compared with noncarriers of the allele with a
normal BMI. 14 These findings suggest that obesity is a
significant risk factor for developing MS in genetically
predisposed individuals.
Inflammation
Previously, it was believed that adipose tissue was
metabolically inactive and its main purpose was storage,
thermal regulation, and protection of vital organs. However,
we now understand that adipose tissue is metabolically active
and highly involved in hormonal and immune functions both
locally and systemically. 20 Adipose tissue consists of the
adipocyte as well as supporting cells, including fibroblasts,
endothelial cells, and immune cells of both innate
(macrophages, neutrophils, eosinophils, and mast cells) and
adaptive (T and B cells) immunity. The adipocyte secretes a
variety of adipokines (signaling proteins specific to
adipocytes), including leptin and adiponectin. Under
conditions of excess weight, adipocytes secrete
proinflammatory cytokines, including tumor necrosis factor
alpha, monocyte chemoattractant protein 1, and interleukin 6.
20
As a result, obesity is considered a chronic proinflammatory
state. This chronic inflammation has been associated with a
variety of disorders including atherosclerosis, diabetes
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mellitus, many types of cancer, inflammatory bowel disease,
and MS.
On a cellular level, the damage that occurs in MS is due to
autoreactive T cells entering the CNS and destroying
oligodendrocytes, cells that produce myelin to insulate
neurons. 21 Furthermore, inflammatory dendritic cells and
macrophages promote disease by activating these autoreactive
T cells and secreting proinflammatory cytokines. The chronic
inflammation associated with obesity leads to unrestricted
activation of the inflammasome, a multiprotein intracellular
complex that secretes proinflammatory cytokines.
21,22
Gut Microbiome
The gut microbiome is composed of microbes, such as
bacteria, viruses, and fungi, that reside in the bowel.
14,23
These
microorganisms contribute to the development of the immune
system, protect against pathogens, and even assist in metabolic
functions of the body both locally and systemically. Stool
samples from patients with MS reveal significantly increased
levels of Methanobrevibacter and Akkermansia and decreased
levels of Butyricimonas (phylum: Bacteroidetes) compared
with controls without MS.
14,24
Methanobrevibacter and
Akkermansia are associated with T cell activation and
proinflammatory cytokines, whereas Butyricimonas are
associated with anti-inflammatory cytokines. Patients with
obesity have also been found to have elevated levels of
Methanobrevibacter and reduced levels of Bacteroidetes.
These correlations in relative levels of microbiome species
support an association between the proinflammatory
environments among patients with obesity and MS.
Leptin and Adiponectin
Leptin is one of the peptide hormones secreted by adipocytes.
It signals satiety, reduces food intake and regulates fat stores.
Patients with obesity are relatively resistant to leptin, so levels
are often found to be elevated. Interestingly, leptin has strong
proinflammatory effects and is also found to be elevated in
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patients with MS. Although there are conflicting findings on
the utility of leptin as a biomarker of MS disease activity,
significantly increased levels have been reported in the
cerebrospinal fluid (CSF) of patients during MS flares or
relapses.
14,25,26
The rise in leptin is thought to be related to
either increased leptin synthesis in the CSF or increased
movement of leptin through a more permeable blood-brain
barrier that might occur during an MS flare. In both obesity
and MS, leptin modulates the immune system toward a
proinflammatory state by secreting proinflammatory cytokines
and downregulating anti-inflammatory cells. 14 There are many
other hormones that regulate appetite and fat storage, which
may be similarly upregulated in both inflammatory conditions.
In contrast to leptin, adiponectin is a hormone produced by the
adipocyte that has anti-inflammatory effects. It has been
shown in animal studies to be protective in autoimmune CNS
inflammation. Mice without adiponectin have greater disease
markers for MS, and when these mice are treated with
adiponectin, there is improvement in these markers.
27
Adiponectin is an important regulator of T cells and could
potentially have clinical implications for treating MS.
Vitamin D
Vitamin D is one of the fat-soluble vitamins. As it is
sequestered in adipose tissue, circulating levels are often lower
in patients with obesity. Vitamin D has been found to have
many effects on the immune system, and low levels of vitamin
D are thought to be a risk factor for the development of MS.
New studies implicate the potential role of vitamin D in
neuroprotection and myelin repair, and research is underway
to determine if vitamin D supplementation among patients
with MS can alter disease progression or rate of relapse.
28,29
Whether vitamin D deficiency and obesity are independent
risk factors for MS or there are other underlying mechanisms
has not yet been elucidated.
Obesity Treatment
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Patients with both MS and obesity often suffer more
pronounced disabilities than patients with MS who are not
obese. In particular, ambulation can be affected early in the
disease process and can severely impact quality of life. 30 In
addition to physical disabilities, patients with MS and obesity
also have higher rates of depression and suicide. 16 As a result,
treating obesity in patients with MS should be a priority to
improve disability and quality of life.
Lifestyle Modifications and Drug-Induced
Weight Gain
Lifestyle interventions, including diet, exercise, and behavioral
modifications, are the foundation of obesity treatment. Many
dietary strategies can be effective for weight loss.
Recommendations should be tailored to a patient’s
preferences, as adherence to diet is associated with greater
weight loss and greater reductions in cardiac risk factors. 31 A
Mediterranean diet can be a good option for patients at high
cardiovascular risk, as it has been shown to reduce the
incidence of major cardiovascular events in this population.
32
A low-glycemic-index diet can curb hunger and decrease
cravings by reducing blood sugar fluctuations. 33 All patients
trying to lose weight should be counseled to limit sugary
drinks, fast food, junk food, and sweets. Registered dietitians
can provide dietary education and customize diet plans.
The American College of Sports Medicine recommends
150 minutes of moderate-intensity aerobic physical activity
(such as brisk walking or tennis) per week, 75 minutes of
vigorous-intensity aerobic physical activity (such as jogging or
swimming laps) per week, or an equivalent combination of
moderate- and vigorous-intensity aerobic physical activity.
34
Episodes should last at least 10 minutes and, if possible, be
spread out through the week. In addition, weight resistance
(muscle strengthening) is recommended at least twice weekly.
Patients with physical limitations should be encouraged to do
what they can even if they cannot meet the recommendations.
Exercise physiologists, physical therapists, and trainers can
provide additional support for patients.
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Behavioral interventions for weight loss include selfmonitoring, such as weighing on a scale at regular intervals
and keeping a food log to track caloric intake. Stress reduction
and adequate sleep can also be helpful for weight loss. Support
can be provided to patients by an interdisciplinary team
including physicians, dietitians, sports physiologists, physical
therapists, psychologists, social workers, and other health care
professionals. As weight maintenance can be more difficult
than initial weight loss, it is important that patients continue
regular follow-up to ensure long-term adherence to their
treatment plan.
Medications can have unpredictable and variable effects on a
patient’s weight, so it is important to balance the benefits of
treatment against the probability of weight gain. 35 Multiple
medications are associated with weight gain, including certain
antidiabetic, antihypertensive, antidepressant, antipsychotic,
antiepileptic, and antihistamine agents, as well as steroids,
contraceptives, and other hormonal agents. 36 Table 11.1
provides an overview of these medications as well as potential
alternative options. When possible, practitioners should utilize
weight-neutral or weight-loss-promoting medications. If there
are no alternative medications, weight gain can be prevented
or lessened by selecting the lowest dose required to produce
clinical efficacy for the shortest duration necessary.
Table 11.1
Medications Associated With Weight Gain, Weight Neutrality, and
Weight Loss
Weight Gain Weight
Neutral/Less
Weight Gain
Weight
Loss
Antidiabetics Insulin α-Glucosidase
inhibitors
GLP-1
agonists
Meglitinides Bromocriptine Metformin
Sulfonylureas Colesevelam Pramlintide
Thiazolidinediones DPP-4 inhibitors SGLT2
inhibitors
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Weight Gain Weight
Neutral/Less
Weight Gain
Weight
Loss
Antihypertensives α-Adrenergic blockers
β-Adrenergic blockers
(atenolol, metoprolol,
nadolol, propranolol)
ACE inhibitors
ARBs
β-Adrenergic
blockers
(carvedilol,
nebivolol)
Calcium
channel
blockers
Thiazides
Antidepressants Lithium
MAOIs
Mirtazapine
SSRIs (paroxetine)
Tricyclic antidepressants
(amitriptyline, doxepin,
imipramine,
nortriptyline)
SSRIs
(fluoxetine,
sertraline)
Bupropion
Antipsychotics Clozapine
Olanzapine
Quetiapine
Risperidone
Aripiprazole
Lurasidone
Ziprasidone
Antiepileptics Carbamazepine
Gabapentin
Pregabalin
Valproic acid
Lamotrigine
Levetiracetam
Phenytoin
Topiramate
Zonisamide
Contraceptives Medroxyprogesterone
acetate
Barrier
methods
IUDs
Surgical
sterilization
Antihistamines First-generation
antihistamines
Second- and
third-generation
antihistamines
Decongestants
= alternatives
Steroids Glucocorticoids Inhaled steroids
Topical steroids
NSAIDs,
DMARDs =
alternatives
Adapted from Igel LI, Kumar RB, Saunders KH, et al. Practical use of
pharmacotherapy for obesity. Gastroenterology. 2017;152(7):1765-1779.
Copyright © 2017 AGA Institute. With permission. ACE, angiotensin-converting
enzyme; ARB, angiotensin II receptor blockers; DMARD, disease-modifying
antirheumatic drug; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide1; IUD, intrauterine device; MAOI, monoamine oxidase inhibitor; NSAID,
nonsteroidal anti-inflammatory drug; SGLT2, sodium-glucose cotransporter 2;
SSRI, selective serotonin reuptake inhibitor.
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Antiobesity Medications
Weight loss achieved by lifestyle modifications alone is often
limited and difficult to maintain. As a result, patients may
require antiobesity medications, bariatric surgery, devices, or
endoscopic bariatric therapies to achieve and maintain
clinically significant weight loss.
Antiobesity pharmacotherapy is one strategy to offset the
changes in appetite and energy expenditure that occur with
weight loss and improve adherence to lifestyle changes.
According to the 2013 American College of
Cardiology/American Heart Association/The Obesity
Society’s guideline for the management of overweight and
obesity in adults and the Endocrine Society’s clinical practice
guidelines on the pharmacologic management of obesity,
pharmacotherapy for obesity can be considered in patients
with a BMI ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 with weightrelated comorbidities, such as hypertension, dyslipidemia, type
2 diabetes, and obstructive sleep apnea.
37,38
As obesity is a chronic disease, most antiobesity medications
are approved for long-term treatment. Many of the antiobesity
medications affect appetite mechanisms, signaling through
serotonergic, noradrenergic, or dopaminergic pathways. They
primarily target the arcuate nucleus of the hypothalamus to
stimulate the anorexigenic pro-opiomelanocortin (POMC)
neurons, which promote satiety.
Medications approved for weight management should be
viewed as useful additions to diet and exercise for patients
who have been unsuccessful with lifestyle changes alone not
substitutions for lifestyle changes. The six most widely
prescribed antiobesity medications approved by the FDA are
phentermine, orlistat, phentermine/topiramate extended release
(ER); lorcaserin; naltrexone sustained release (SR)/bupropion
SR; and liraglutide 3.0 mg.
39-41
Table 11.2 provides an
overview of the medications. In addition to producing weight
loss, each medication improves metabolic biomarkers,
including blood pressure, blood sugar, and lipids. The four
agents approved since 2012 have stopping rules, which
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