TEM 1783 No.

of Pages 3

Trends in
Endocrinology & Metabolism
Forum
The obese brain: is it a organs, due to low and biased availability
of biological samples, scarceness of longi-
ranging from a few days to a more standard
2–3 months obesogenic diet feeding proto-
matter of time? tudinal studies, and technical limitations col, typically beginning after sexual maturity
linked with postmortem analyses and non- (2 months of age). Direct age equivalences
Ambica Bora1 and invasive imaging. Albeit imperfect, these between mice and humans are obviously
Alexandre Fisette 1,*,@ studies have highlighted obesity-driven imperfect, as the relation between their
structural changes in the human brain, rates of aging is not linear, with mice aging
which revolve around three major con- especially fast in the first postnatal month
Understanding how obesity rewires cepts, specifically the presence of signifi- [7]. Nonetheless, it is conceivable to consider
the brain, triggers neuroinflamma- cant neuroinflammation, brain rewiring, as a 2-month-old mouse to be at a maturational
tion and neurodegeneration relies well as the induction of neurodegeneration. stage comparable with that of a 16- to 18-
on research using animal models. year-old human (Figure 1). After a typical
There is, however, a disconnect Neuroinflammation manifests in the form of obesogenic diet intervention of 2–3 months,
between the timeline of human obe- gliosis, which is a natural defense mecha- at 4–5 months of age, the mouse can then
sity and typical preclinical proto- nism of the brain. A chronic state of systemic be likened to a 25- to 28-year-old adult.
cols. We emphasize here the need inflammation, as observed in obesity, how- Although the use of such a mouse model
ever, induces dystrophic effects on brain of diet-induced obesity is practical and
to adopt models of chronic obesity
matter, particularly in the hypothalamus [4]. cost-efficient, it does not reproduce the
to study the pathophysiology of
In turn, researchers have hypothesized that typical timeline of human obesity.
human obesity.
alterations in hypothalamic gray matter vol-
ume could be due in part to strengthening Humans can live with obesity throughout
of circuits involved in food motivation and re- most of their life. In the USA, approxi-
Obesity is a brain disease duced connectivity in areas associated with mately 40% of young adults are obese,
The prevalence of obesity has reached cognitive control [5]. Finally, decline in gray and will in most cases go on to live with
alarming levels, where close to half the matter volume and white matter in other re- this health burden for many decades. To
world’s population have overweight or gions, involved in executive function and re- model a 45-year-old adult that has been
obesity. Evidences gathered in the past de- ward circuitry, has also been linked with obese for 20 years, we propose that a
cades convincingly demonstrate that obe- obesity [6], hinting that this obesity induced representative preclinical mouse model
sity is first and foremost a disease of the feed-forward cycle culminates into cognitive would have to show signs of obesity at
central nervous system [1]. Genome-wide impairment. approximately 3 months of age, and to
association studies have consequently be examined at 10 months of age, after
shown that polymorphisms most strongly Deeper molecular profiling of the circuits roughly 7 months of obesity (Figure 1).
correlated with obesity are located within and cell types involved in body weight The length of such a diet-induced obesity
genes that are highly enriched in the brain homeostasis still currently relies on further protocol in mice is unfortunately unusual
[2]. A respectable molecular understanding studies in animal models. Are these in the literature.
of the diverse neuronal networks in charge changes causally linked with obesity, or a
of maintaining body weight was achieved in consequence of sustained positive energy The knowledge scientists have garnered
large part due to the use of animal models balance? Which neuronal populations, so far in mice through most obesity stud-
in preclinical obesity research, which aims specifically, are most affected, and how? ies remains important; however, it is more
to mimic human pathophysiology. These likely to contribute to our understanding
systems, whether linked with hypothalamic Modeling obesity in mice of short-term adaptations to energy sur-
homeostatic regulation or limbic reward cir- Answering the aforementioned questions plus rather than long-term, enduring
cuitry, are known to be highly conserved raised by observing human obesity is changes in brain structure and function
among mammals, and models of mono- complex and requires functional studies as observed in humans. The underlying
genic and polygenic obesity in mice closely performed in preclinical models, with the questions naturally stemming from this as-
resemble human disease [3]. house mouse (Mus musculus) being one of sertion are what neural adaptations and
the most frequently used species. The changes consequent to long-term diet-
The obese brain conventional approach regarding preclinical induced obesity are we currently missing
The study of the human brain is extraordi- diet-induced obesity research in mice with our short-term approach, and how
narily complex in comparison to most focuses on short-term diet interventions relevant are they?

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 Trends in Endocrinology & Metabolism

human obesity, and uncovered radical

Timeline of mouse & human obesity
changes in their biology. Indeed, long-term
diet-induced obesity (≥6 months) has been
shown to severely affect Pomc neurons,
Human age (years) which become dysfunctional. Although not
50
Mouse age (months) evident in shorter preclinical studies, such
Average age for long-term obesogenic protocols in mice
bariatric surgery 45
12 lead to a substantial reduction of 25–50%
Pomc neuron of Pomc-positive neurons in the hypothala-
dysfunction
mus [4]. Such changes, akin to partial
40
10 Pomc neurons depletion, could radically im-
pair the organism’s homeostatic capacities,
yet the underlying causes and conse-
35 quences remain obscure.
8 Middle-aged

Other circuits and biological phenomenon

Middle-aged outside of the melanocortin system are
30
6 also differentially affected by the duration of
obesity. Specific neuronal populations such
25 as orexin neurons, within the lateral hypo-
thalamus, exhibit time- and diet-dependent
4
rewiring and changes in numbers [9]. Neu-
roinflammation inside the hypothalamus
20
follows a biphasic development, wherein in-
2 Adult
flammation is quickly resolved after a few
Adult weeks of high-fat feeding, only to resurge
durably after several months of diet-
Short-term Long-term induced obesity [4,10]. Beyond the hypo-
Non-obese
phase adaptations adaptations thalamus, other brain regions linked with
to obesity to obesity
the rewarding effect of food and drugs can
Trends in Endocrinology & Metabolism
also be differentially affected by prolonged
Figure 1. Timeline of mouse and human obesity. Schematic representing the typical timeline of human
obesity. While a set of adaptations occurs
obesity, compared with the potential timeline of diet-induced obesity (DIO) in mouse models, along with select within the dopaminergic system with short-
obesity ‘milestones’. Current preclinical diet-induced obese mouse models preponderantly adopt short-term term exposure to energy-dense, palatable
diet protocols of 2–3 months; enough to investigate short-term adaptations to obesity, but insufficient to diets, other parameters are dependent on
assess long-term adaptations. Abbreviation: Pomc, pro-opiomelanocortin.
the overall degree of adiposity, and thus
diet duration [11]. Notably, substance use
disorders with respect to drugs of abuse
are multistage diseases which are affected
Time matters: the melanocortin, Metabolic stress during short-term diet- by the length of exposure. Similarly, food-
orexigenic, and dopaminergic induced obesity (≤3 months) affects the related ‘addiction’ is thought to resemble
systems melanocortin system in multiple ways. substance use disorders, which under-
One highly relevant circuit that is deeply Importantly, although there is an increasing scores that it is likely a multistage disease
and specifically affected by long-term presence of apoptotic markers along with with different layers of alterations emerging
obesity is the melanocortin system of the physiological changes that may disrupt the in the reward system depending on the
hypothalamus. This system is composed function of Pomc neurons, their total cell length of exposure [12]. Overall, the dura-
of neuronal populations expressing pro- number remains unchanged [8]. In turn, tion of obesity in mouse models deter-
opiomelanocortin (Pomc) or agouti-related some studies have looked at Pomc neurons mines the nature and extent of the
protein (Agrp), which play antagonistic after a much longer period of high-fat diet observed brain alterations. The most signif-
roles in energy homeostasis. feeding, which we emphasize better mimics icant changes involving neuroinflammation,

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Trends in Endocrinology & Metabolism

neurodegeneration, or rewiring – hallmarks of chronic obesity. It is unclear whether from NSERC (RGPIN-2022-05206), Brain Canada
of the human obese brain – thus manifest the long-term molecular consequences of (Future Leaders in Canadian Brain Research 2021),
predominantly in mouse models of pro- obesity observed in mice, such as Pomc as well as by the Université du Québec à Trois-
Rivières. The figure was created with BioRender.com.
longed, long-term obesity. neurons loss, can be rescued by such sur-
gical or nutritional, including low-calorie or
Declaration of interests
Concluding remarks and future ketogenic diets, interventions. Moreover, No interests are declared.
perspectives the effects of different types of diets on
That our current preclinical approach in the long-term consequences of obesity 1Research Group in Cellular Signaling, Department of Medical
mouse models overlooks many aspects of have not been fully investigated; whether Biology, Université du Québec à Trois-Rivières, Trois-Rivières,
the pathophysiology of human obesity is high-fat and western diets, for example, Québec, Canada
not necessarily shocking, as many diseases similarly affect the neuropathology of obe- *Correspondence:
are hard to replicate in short-lived animal sity is of high interest. alexandre.fisette@uqtr.ca (A. Fisette).
@
Twitter: @Physettes
models. To overcome this limitation, the
https://doi.org/10.1016/j.tem.2023.08.003
use of leptin-deficient or leptin receptor- Ultimately, the biological systems and cir-
dysfunctional transgenic mice (Lepob/Lepob cuits that could be taken advantage of may © 2023 Elsevier Ltd. All rights reserved.
and Leprdb/Leprdb models) is frequent, as not be fully, or similarly, functional in long-
they become obese at early age even on term obesity, as we made a case with the References 1. Caron, A. and Jane Michael, N. (2021) New horizons: is
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elicit weight loss and improve health. In Acknowledgments croglia, and tanycytes in brain control of systemic metabo-
lism. Nat. Neurosci. 22, 7–14
addition, functional magnetic resonance We thank Ismael González-García for helping us criti-
11. Décarie-Spain, L. et al. (2016) Dopamine signalling adapta-
imaging (fMRI) studies in humans have re- cally improve this manuscript. A.F. holds a Junior Re- tions by prolonged high-fat feeding. Curr. Opin. Behav. Sci.
ported rapid and positive changes in the search Chair in Neurometabolism from Université du 9, 136–143
Québec à Trois-Rivières and is funded via a salary 12. Gordon, E. et al. (2018) What is the evidence for “food
brain after bariatric surgery, indicating that addiction?” a systematic review. Nutrients 10, 477
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weight loss and altered hormonal milieu Santé (FRQS); A.B. is funded via a doctoral fellowship
can ‘rescue’ at least partially the central from the Université du Québec à Trois-Rivières (PAIR
nervous system from the consequences program to A.F.). A.F. research is funded by grants

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