Lateral Hypothalamic Control of Energy Balance

by Gizem Kurt, Hillary L. Woodworth, Gina

Lateral Hypothalamic Control of Energy Balance Food and water are necessary for survival but can only be obtained via ingestive behavior feeding drinking and moving Survival thus depends on the ability of the brain to coordinate the need for water and energy with appropriate behaviors to modify their intake as necessary for homeostasis However the balance of these behaviors also inherently determines body weight and imbalances contribute to the development of weight disorders such as obesity and anorexia nervosa The lateral hypoth

Publisher : Morgan amp

Author : Gizem Kurt, Hillary L. Woodworth, Gina M. Leinninger

ISBN : 9781615047659

Year : 2017

Language: en

File Size : 1.9 MB

Category : Science Math

Lateral Hypothalamic Control
of Energy Balance

ii

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Colloquium Series on
Integrated Systems Physiology:
From Molecule to Function to Disease
Editors
D. Neil Granger, Louisiana State University Health Sciences Center
Joey P. Granger, University of Mississippi Medical Center
Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses
function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the
processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology
that account for the relative constancy of organ processes and bodily function even in the face of
substantial environmental changes. This constancy results from integrative, cooperative interactions
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Lateral Hypothalamic Control of Energy Balance
Gizem Kurt, Hillary L. Woodworth, and Gina M. Leinninger
www.morganclaypool.com
ISBN: 9781615047659 paperback
ISBN: 9781615047666 ebook
ISBN: 9781615047673 hardcover
DOI: 10.4199/C00159ED1V01Y201711ISP079
A Publication in the
Colloquium Series on Integrated Systems Physiology: From Molecule to
Function to disease
Lecture #79
Series Editors: D. Neil Granger, LSU Health Sciences Center, and Joey P. Granger, University of  Mississippi
Medical Center
Series ISSN
ISSN 2154-560X

print

ISSN 2154-5626

electronic

Lateral Hypothalamic Control
of Energy Balance
Gizem Kurt
Department of Physiology
Michigan State University

Hillary L. Woodworth
Department of Physiology
Michigan State University

Gina M. Leinninger
Department of Physiology
Michigan State University

COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY:
FROM MOLECULE TO FUNCTION TO DISEASE #79

vi

ABSTRACT
Food and water are necessary for survival, but can only be obtained via ingestive behaviors
(feeding, drinking, and moving). Survival thus depends on the ability of the brain to coordinate
the need for water and energy with appropriate behaviors to modify their intake as necessary
for homeostasis. However, the balance of these behaviors also inherently determines body weight,
and imbalances contribute to the development of weight disorders, such as obesity and anorexia
nervosa. The lateral hypothalamic area (LHA) of the brain is anatomically positioned to coordinate the sensation of osmotic and energy status with goal-directed ingestive behaviors necessary to maintain homeostasis and body weight, and, hence, may hold insight into the potential
treatment for energy balance disorders. This volume reviews the essential role of the LHA for
the control of body weight, from its historical description as a “feeding center” to the current
view of this LHA as a cellularly heterogeneous hub that regulates multiple aspects of physiology
to influence body weight. Furthermore, we evaluate how specific LHA populations coordinate
certain metabolic cues and behaviors, which may guide the development of pathway-specific
interventions to improve the treatment of energy balance disorders.

KEYWORDS:
lateral hypothalamic area, energy balance, body weight regulation, orexin, hypocretin, melanin
concentrating hormone, neurotensin, ingestive behavior

vii

Contents
1. The Weighty Implications of  the Lateral Hypothalamic Area
in Energy Balance................................................................................................1
1.1 Homeostasis and Body Weight............................................................................ 1

1.2
1.3
1.4
1.5

What Is Energy Balance and How Does It Relate to Health?................... 2
Obesity Is a Disease of Disrupted Energy Balance.................................... 4
The Brain Coordinates Energy Balance..................................................... 9
Discovery of a Role for the Lateral Hypothalamic Area (LHA)
in Energy Balance.................................................................................... 10
1.6 “Lateral Hypothalamic Syndrome” Suggests an Essential Role
for the LHA in Coordinating Behavior................................................... 12
1.7 Physiologic and Pharmacologic Regulation of the LHA......................... 14
1.8 Neuronal Diversity in the LHA and Implications for
Energy Balance........................................................................................ 15
2.

Anatomy and Connectivity of the LHA .............................................................. 17
2.1 Location of the LHA and Implications for its Function.................................... 17
2.2 Molecularly Defined Populations of Neurons Within the LHA........................ 19
2.2.1 Overview of LHA Subpopulations......................................................... 19
2.2.2 Melanin-concentrating Hormone (MCH)............................................. 19
2.2.3 Orexin/Hypocrectin (OX)...................................................................... 22
2.2.4 Neurotensin (Nts)................................................................................... 23
2.2.5 Galanin (Gal)......................................................................................... 23
2.2.6 GABA.................................................................................................... 25
2.2.7 Glutamate............................................................................................... 25
2.2.8 Receptor Expressing Populations (LepRb, MC4R)............................... 25
2.2.9 Other Populations of LHA Neurons...................................................... 26
2.3 Afferents to the LHA......................................................................................... 26
2.3.1 Hypothalamic Arcuate Nucleus (ARC).................................................. 26

viii  Lateral Hypothalamic Control of Energy Balance

2.3.2 Hypothalamic Ventromedial Nucleus (VMH)....................................... 27
2.3.3 Parabrachial Nucleus (PB)...................................................................... 27
2.3.4 The Bed Nucleus of the Stria Terminalis (BNST)................................. 28
2.3.5 Nucleus Accumbens (NA)...................................................................... 28
2.3.6 Regions Involved in Learning and Memory (Prefrontal Cortex,
Amygdala, Hippocampus, and Septum)................................................. 29
2.3.7 Lamina Terminalis (LT)......................................................................... 29
2.4 Projections from the LHA................................................................................. 30
2.4.1 The Ventral Tegmental Area (VTA)...................................................... 30
2.4.2 The Nucleus Accumbens (NA).............................................................. 32
2.4.3 Lateral Habenula (LHb)........................................................................ 32
2.4.4 Regions Involved in Learning and Memory (Prefrontal Cortex,
Amygdala, and Hippocampus)................................................................32
2.4.5 Lamina Terminalis (LT)......................................................................... 33
2.4.6 Preoptic Area (POA).............................................................................. 33
2.4.7 Hypothalamic Paraventricular Nucleus (PVH)...................................... 33
2.4.8 Local Projections Within the LHA....................................................... 34
2.5 Peripheral Regulators of LHA Neurons............................................................. 34
2.5.1 Leptin..................................................................................................... 34
2.5.2 Ghrelin................................................................................................... 35
2.5.3 Glucose................................................................................................... 35
2.5.4 Dehydration............................................................................................ 36
3.

Roles of LHA Neurons in Regulating Feeding..................................................... 39
3.1 Overview of the LHA in Control of Feeding..................................................... 39
3.2 Melanin-Concentrating Hormone (MCH) Neurons in Control
of Feeding........................................................................................................... 40
3.3 Orexin (OX) Neurons in Control of Feeding..................................................... 41
3.4 Neurotensin (Nts) Neurons in Control of Feeding............................................. 43
3.5 Galanin (Gal) Neurons in Control of Feeding................................................... 45
3.6 Corticotropin Releasing Hormone (CRH) Neurons in Control
of Feeding........................................................................................................... 45
3.7 GABA Neurons in Control of Feeding.............................................................. 46
3.8 Glutamate Neurons in Control of Feeding......................................................... 48

contents  ix

4.

Role of the LHA in Drinking Behavior................................................................ 49
4.1 Overview of the LHA in Control of Drinking.................................................. 49
4.2 Melanin-Concentrating Hormone (MCH) Neurons in Control
of Drinking......................................................................................................... 50
4.3 Orexin (OX) Neurons in Control of Drinking................................................... 50
4.4 Neurotensin (Nts) Neurons in Control of Drinking........................................... 51
4.5 CRH Neurons in Control of Drinking............................................................... 52
4.6 GABA and Glutamate Neurons in Control of Drinking................................... 52

5.

Role of the LHA in Arousal, Physical Activity, and Energy Expenditure............... 55
5.1 Overview of the LHA in Control of Basal and Volitional Energy
Expenditure........................................................................................................ 55
5.2 Melanin-Concentrating Hormone (MCH) Neurons in Control of
Energy Expenditure........................................................................................... 56
5.3 Orexin (OX) Neurons in Control of Energy Expenditure.................................. 57
5.4 Neurotensin (Nts) Neurons in Control of Energy Expenditure......................... 58
5.5 Galanin (Gal) Neurons in Control of Energy Expenditure................................ 59
5.6 GABA and Glutamate Neurons in Control of Energy Expenditure.................. 59

6.

Role of the LHA in Human Physiology............................................................... 61
6.1 What Have 60 Years of LHA Studies in Animals Taught Us About Human
Energy Balance?................................................................................................. 61
6.2 Role of Melanin-Concentrating Hormone (MCH) in Human
Energy Balance and Disease............................................................................... 62
6.3 Role of Orexin (OX) in Human Energy Balance and Disease........................... 62
6.4 Role of Neurotensin (Nts) in Human Energy Balance and Disease................... 64
6.5 Role of GABA and Glutamate in Human Energy Balance and Disease........... 65

References.................................................................................................................. 67
Author Biographies................................................................................................... 105



chapter 1

The Weighty Implications of
the Lateral Hypothalamic Area
in Energy Balance
1.1

Homeostasis and Body Weight

Perhaps, the most fundamental theme of physiology is homeostasis: the maintenance of a relatively stable internal environment necessary to support life. Two essential components for homeostasis are adequate stores of energy (derived from caloric intake) and fluid (water), both of
which are essential for cell, system, and bodily health. However, the very physiologic processes
used to sustain life (e.g., respiration, thermogenesis, movement, digestion) constantly tap bodily
reserves of energy and water so that they must be continually replenished. Because food and
water cannot be synthesized within the body, they must be replaced via ingestion. Preservation
of energy and fluid homeostasis, thus, requires that animals constantly assess their internal environment, detect need for energy and/or water, and then execute the appropriate feeding and/
or drinking behaviors to obtain these resources from the environment. The feelings of hunger
and thirst serve to communicate the body’s need for food and water to the brain so that it can
coordinate the appropriate ingestive behavior (feeding or drinking) to restore homeostasis. An
important byproduct of this process is the regulation of body weight, which is a visible proxy for
homeostasis and whether adequate resources are available to support bodily health. For example, fasting-induced hunger or dehydration-induced thirst increase the motivation to find and
ingest food and water, respectively [1, 2]. Failure to obtain these resources results in acute weight
loss that initially strengthens the drives to obtain them, and to avoid prolonged depletion of
energy and fluid reserves that would compromise survival. Resource excess is coordinated with
behavioral responses to limit intake: stomach fullness or increased body fat cue the cessation
of feeding [3, 4], whereas plasma hypotonicity biases for salt versus water intake to restore fluid
homeostasis [5]. Thus, individuals vigilantly monitor fluid and energy status and coordinate ap­
propriate ingestive behaviors that impact body weight and survival. Although work over the

  Lateral Hypothalamic Control of Energy Balance

past decades indicates that the brain is crucial for orchestrating drive states, behavior, and body
weight, the precise neural circuits underlying these processes remain incompletely understood.
Herein, we will address the role of a particular part of the brain, the lateral hypothalamic area
(LHA), in coordinating energy balance, homeostasis and, hence, in the physiology underlying
health and survival.

1.2

What Is Energy Balance and How Does
It Relate to Health?

Energy homeostasis is often referred to and illustrated as “energy balance,” to convey the inter­
dependent relationship between energy intake and expenditure that determines body weight
and health (Figure 1A). Energy intake consists of calories consumed through food and caloricliquids, such as milk, juices, or sugar-laden sports drinks and soda. Energy expenditure refers
to the calories that are consumed by the body to support basal metabolism and behavior, in
the form of voluntary physical activity. For most individuals, energy expenditure is the sum of
their resting metabolic rate (RMR), the thermic effect of feeding (TEF), and the thermic effect
of activity (TEA) [6]. RMR comprises 60% to 75% of total energy expenditure and is the energy
required by the body to perform basic physiologic functions, or more simply the “number of
calories an individual would use if he/she stayed in bed all day.” The TEF accounts for 10% of
energy expenditure and is the energy required for digesting food. The TEA can account for
15% to 30% of an individual’s energy expenditure and refers to the additional calories burned
through volitional activity and exercise [6]. When energy intake exceeds expenditure, it creates
a caloric surfeit, or “positive energy balance,” which can be stored in the body as fat and lead to
weight gain (Figure 1B). Conversely, when energy expenditure exceeds caloric intake, the body
experiences a caloric deficit or “negative energy balance”; as a result, calories required to support
survival are obtained from adipose reserves, leading to weight loss (Figure 1C).
At face value, energy balance appears to be a simple math equation, but its coordination
is complex, requiring continuous communication between the periphery (to sense energy status) and the brain (to modulate energy intake and expenditure, as necessary). Energy balance
is intimately tied to the idea of a body weight “set-point” wherein genetic and environmental factors determine an individual’s body weight, which is defended through homeostatic
mechanisms that compensate for positive or negative energy balance [7]. For example, in controlled over-feeding studies, total energy expenditure increases and appetite decreases as the
body attempts to deplete the caloric surplus [8, 9]. Similarly, weight loss leads to increased

Weighty Implications of  the Hypothalamic Area in energy balance  

Figure 1: Energy Balance. (A) The interdependent relationship between energy intake and expenditure
that determines body weight. (B) Positive energy balance with increased energy intake and decreased energy
expenditure leading to weight gain. (C) Negative energy balance with decreased energy intake and increased
energy expenditure leading to weight loss.

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